IPSS-m outperforms IPSS-R in younger adults with Myelodysplastic Syndromes: A retrospective age-stratified analysis

Abstract Introduction Myelodysplastic syndromes (MDS) predominantly affect older adults, with a median age at diagnosis over 70 years, and fewer than 10% of cases occurring before age 50. Aging is associated with clonal hematopoiesis and an increased prevalence of epigenetic mutations (e.g., TET2, ASXL1). Younger adults with MDS (<50 years) remain understudied and may exhibit distinct molecular and clinical features. This study evaluated whether the molecularly integrated Molecular International Prognostic Scoring System (IPSS-M) provides improved prognostic discrimination in younger patients compared to the conventional Revised International Prognostic Scoring System (IPSS-R). Methods We retrospectively analyzed 202 adult MDS patients consecutively diagnosed at West China Hospital between January 2015 and December 2022. Patients were dichotomized by age: <50 years (n=53) and ≥50 years (n=149). Clinical, laboratory, cytogenetic, and targeted next-generation sequencing data (including mutations in DNMT3A, ASXL1, TET2) were collected. Risk stratification was performed using both IPSS-R and IPSS-M. Overall survival (OS) was estimated via Kaplan–Meier analysis and compared using the log-rank test. Group differences were assessed using χ² or Fisher's exact tests for categorical variables, and t-tests or Mann–Whitney U tests for continuous variables. Results The median age was 58 years. Baseline hematologic parameters, cytogenetic risk, and World Health Organization/International Consensus Classification did not significantly differ between age groups (all p > 0.05). Older patients had more comorbidities, notably cardiovascular disease (29.5% vs. 7.5%, p < 0.05). Younger patients were more likely to undergo allogeneic stem cell transplantation (32.1% vs. 8.7%), while older patients more often received hypomethylating agents (59.1% vs. 35.8%). Genetically, mutations in the age-associated DAT gene cluster (DNMT3A, ASXL1, TET2) were significantly less frequent in younger patients (14.5%) compared to older patients (32.5%, p = 0.005). Specifically, TET2 and ASXL1 mutations were enriched in the older cohort (p < 0.001 and p = 0.034, respectively). Median OS was significantly longer in younger patients (17.2 vs. 13.6 months, p < 0.05). Prognostic discrimination by age subgroup revealed distinct patterns. Among older patients (≥50 years; n=149), both IPSS-R and IPSS-M stratified OS significantly. For IPSS-M, the extremely high-risk group (n=70) had a median OS of 15.0 months vs. 30.6 months in the non-extremely high-risk group (n=79, p < 0.0001). For IPSS-R, median OS was 18.6 vs. 29.5 months between extremely high-risk (n=68) and non-extremely high-risk groups (n=81, p = 0.015). In contrast, among younger patients (<50 years; n=53), only IPSS-M effectively separated survival risk. The extremely high-risk group (n=30) had a median OS of 14.9 months, while the non-extremely high-risk group (n=23) had not reached median OS (p = 0.0078). IPSS-R failed to distinguish OS in this cohort (median OS: 30.2 vs. 36.4 months, p = 0.27). These findings underscore the enhanced prognostic accuracy of IPSS-M in younger patients, where it identifies individuals with aggressive disease biology more precisely and avoids over-assignment to the intermediate-risk stratum. Conclusions Younger adults with MDS represent a biologically distinct subgroup, characterized by significantly fewer age-related mutations in DAT genes. In this population, the IPSS-M scoring system offers superior prognostic resolution compared to IPSS-R, particularly in distinguishing truly high-risk disease. Our results suggest that IPSS-M should be the preferred risk model for younger patients with MDS, enabling more accurate survival prediction and guiding clinical decisions such as early transplantation. Age-stratified application of molecular risk tools may enhance personalized management in adult MDS.