Improving MDS Risk Assessment: The Role of Monocytopenia and Lymphocytopenia Beyond IPSS-R

<i>Background and Objectives</i>: The revised international prognostic scoring system (IPSS-R) remains the most widely used prognostic tool for myelodysplastic syndrome (MDS). There is growing evidence that inflammation and immunological dysregulation are important in the pathogenesis of MDS. Moreover, monocytopenia and lymphocytopenia are correlated with adverse outcomes in patients with MDS. However, standard guideline-driven diagnostic and prognostic models do not evaluate host immunity parameters. This study explored the prognostic relevance of monocytopenia and lymphocytopenia at diagnosis for overall survival (OS) as medical endpoints independent of IPSS-R. <i>Materials and Methods:</i> This retrospective study included 217 patients with MDS diagnosed and treated at the University Clinical Center of Serbia between July 2019 and July 2024. MDS was diagnosed based on the 2016 World Health Organization (WHO) criteria. <i>Results</i>: Univariate analysis revealed that patients with monocytopenia (absolute monocyte count (AMC) < 0.3 × 10⁹/L) had adverse outcomes compared to individuals with normal AMC (AMC ≥ 0.3 × 10⁹/L) (median OS with/without risk factor 20 months vs. 60 months, respectively, log rank test <i>p</i> = 0.0009). Moreover, lymphocytopenia (absolute lymphocyte count (ALC) < 1.2 × 10⁹/L) was shown to have a significant impact on survival (median OS with/without risk factor 17 months vs. 29 months, respectively; log-rank <i>p</i> = 0.0182). In further multivariate analysis, IPSS-R, AMC < 0.3 × 10⁹/L, ALC < 1.2 × 10⁹/L, and DMAs/HSCT were identified as independent prognostic factors for OS (Cox multivariate model, <i>p</i> < 0.001, <i>p</i> = 0.0237, <i>p</i> = 0.006, <i>p</i> < 0.001, respectively). <i>Conclusions:</i> Our findings suggest that ALC and AMC can serve as readily accessible and verifiable prognostic tools in MDS at presentation. Combined with IPSS-R, these markers may provide additional prognostic insights, enabling better risk stratification in MDS patients who could benefit from future immunotherapies.