Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Area of Science:

• Hematology
• Oncology
• Genomics
• Medical Informatics

Background:

• Current risk stratification for myelodysplastic syndromes (MDS) relies on the International Prognostic Scoring System–Revised (IPSS-R), which uses hematologic and cytogenetic data.
• Somatic gene mutations are not yet incorporated into MDS risk assessment, limiting prognostic accuracy.

Purpose of the Study:

• To develop and validate a novel clinical-molecular prognostic model, the IPSS-Molecular (IPSS-M), for patients with MDS.
• To integrate genomic mutation data with clinical and cytogenetic factors for improved risk stratification and therapeutic decision-making in MDS.

Main Methods:

• Somatic mutations in 152 genes were profiled in pretreatment samples from 2957 MDS patients.
• Clinical and molecular variables were analyzed for associations with leukemia-free survival, leukemic transformation, and overall survival using multivariable Cox models.
• The IPSS-M was validated in an independent cohort of 754 Japanese MDS patients.

Main Results:

• Genomic alterations were identified in 94% of MDS patients, with TP53, FLT3, and MLLPTD mutations predicting adverse outcomes, while SF3B1 mutations indicated favorable outcomes.
• The IPSS-M, incorporating 31 genes, hematologic parameters, and cytogenetics, provided improved prognostic discrimination and reclassified 46% of patients compared to IPSS-R.
• An open-access Web calculator was developed to facilitate clinical use of the IPSS-M.

Conclusions:

• The IPSS-M enhances risk stratification for MDS by integrating genomic profiling with established clinical and cytogenetic parameters.
• This molecularly informed model offers a valuable tool for personalized therapeutic decision-making in MDS patients.
• The IPSS-M demonstrates applicability in both primary and secondary/therapy-related MDS.