Thrombocytopenia at diagnosis adversely affects overall and leukemia-free survival in lower-risk MDS patients: A retrospective study from the FISiM registry

Abstract Background Thrombocytopenia is a frequent hematologic abnormality in patients with myelodysplastic syndromes (MDS), occurring in approximately 40–60% of cases. It has been consistently associated with adverse clinical outcomes and is incorporated into the Revised International Prognostic Scoring System (IPSS-R), where platelet (PLT) counts <100,000/mm³ indicate a higher-risk disease category. In patients with lower-risk MDS (LR-MDS), the prognostic significance of thrombocytopenia is less well defined but has been incorporated in a prognostic model by the MD Anderson Cancer Center together with anemia, age, marrow blast percentage, and cytogenetic risk (Garcia-Manero G et al. Leukemia 2008). The objective of this study was to evaluate the prognostic impact of thrombocytopenia at diagnosis on overall survival (OS) and leukemia-free survival (LFS) in a large cohort of patients with LR-MDS enrolled in the registry of the Italian Foundation for the Study of Myelodysplastic Syndromes (FISiM). Methods We retrospectively analyzed clinical and hematologic data from patients diagnosed with LR-MDS between January 1, 2007, and October 29, 2024, and included in the nationwide FISiM registry. All patients were classified according to the 2016 WHO diagnostic criteria. Categorical variables were compared using the chi-square test. OS and LFS were estimated using the Kaplan-Meier method and compared by log-rank test. Cox proportional hazards regression models were used for multivariate analyses to identify variables independently associated with outcomes. A two-tailed p-value <0.05 was considered statistically significant. Results A total of 2,213 patients with LR-MDS were included in the analysis. Of these, 610 patients (27.6%) presented with PLT counts <100,000/mm³ at diagnosis, while 1,603 (72.4%) had counts ≥100,000/mm³. The cohort comprised 1,314 males and 899 females, with a median age of 75 years (range: 19–98). The median follow-up was 32.1 months. The overall median OS was 80.0 months, with 1-, 2-, and 3-year OS rates of 96%,87% and78%, respectively. According to WHO classification, MDS with multilineage dysplasia (MDS-MLD) was the most common subtype in the thrombocytopenic group (61% vs. 38%), followed by MDS with single-lineage dysplasia (15% vs. 28%). In univariate analysis, thrombocytopenia was significantly associated with inferior OS and LFS (p<0.001 for both comparisons). This finding was also correlated with low megakaryocyte cellularity and megakaryocytic dysplasia. Interestingly, thrombocytopenia was more frequently observed in patients with hemoglobin levels >10 g/dL, suggesting it may define a distinct biological subgroup. In multivariate analysis, PLT <100,000/mm³ remained an independent predictor of worse OS (hazard ratio [HR] 1.25; 95% confidence interval [CI]: 1.15–1.37; p<0.001), along with older age, female sex, hemoglobin <10 g/dL (all p<0.001), and marrow blasts ≥5% (p=0.003). Leukemic transformation occurred in 65 patients (10.7%) in the thrombocytopenic group and in 131 patients (8.2%) with PLT ≥100,000/mm³ (p=0.06). The median time to progression was significantly shorter in thrombocytopenic patients: 139.5 months (95% CI: 129.3–149.7) vs. 155.7 months (95% CI: 149.6–161.8); p=0.005. Overall, 723 patients (32.7%) died, with a higher mortality observed in the thrombocytopenic group (36.4% vs. 31.3%). In the multivariate analysis for LFS, PLT <100,000/mm³ remained an independent adverse factor (HR: 1.20; 95% CI: 1.02–1.40; p=0.03), together with female sex (p=0.003) and blast count ≥5% (p<0.001). Conclusions Our study confirms that thrombocytopenia at diagnosis is an independent predictor of worse overall and leukemia-free survival in patients with lower-risk MDS. These findings underscore the importance of incorporating platelet count into risk stratification strategies even within the LR-MDS population. Closer monitoring and potentially earlier therapeutic intervention should be considered in this subgroup to improve clinical outcomes.