New Prognostic Scoring System for MDS Incorporates Somatic Gene Mutations

An international team of researchers has developed a clinical-molecular prognostic model that offers an improved scoring system for myelodysplastic syndromes (MDS).

For the past 10 years, risk stratification and therapeutic decision-making for MDS has been based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities but not somatic gene mutations, which have been shown to be valuable prognostic biomarkers.

The new IPSS-Molecular (IPSS-M) model, in contrast, generates a unique risk score for individual patients that incorporates hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes and classifies patients into six risk categories with prognostic differences.

To create the model, the team profiled pretreatment diagnostic or peridiagnostic samples from 2,957 patients with MDS for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival.

The team then applied feature selection to determine the set of independent IPSS-M prognostic variables and estimated the relative weights of the selected variables using a robust Cox multivariable model adjusted for confounders.

The team was able to map at least one oncogenic genomic alteration in 94% of patients with MDS and identified TP53^multihit, FLT3 mutations, and MLL^PTD as top genetic predictors of adverse outcomes.

The researchers validated the model in an external cohort of 754 Japanese patients with MDS. Compared with IPSS-R, the IPSS-M model improved prognostic discrimination across all clinical endpoints and restratified 46% of patients.

“Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making,” the authors wrote.

Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evidence. 2022; 1(7). doi:10.1038/p.EVIDoa2200008