Unveiling relative lymphopenia and elevated monocyte-to-lymphocyte count as novel independent adverse prognostic factors in chronic myelomonocytic leukemia (CMML)-Proposal of the objective prognostic index for CMML (OPIC).

Chronic myelomonocytic leukemia (CMML) shows marked prognostic heterogeneity. Although leukocytosis is a recognized adverse prognostic factor, the contribution of its individual components remains insufficiently defined. In a cohort of 240 patients classified according to International Consensus Classification (ICC) and World Health Organization (WHO) 2022 criteria-including 23% with oligomonocytic CMML-we evaluated the prognostic impact of neutrophil and monocyte percentage, along with surrogate markers of their relative increase, including relative lymphopenia (<20%) and elevated monocyte-to-lymphocyte ratio (MLR > 1). Both relative lymphopenia and MLR > 1 emerged as independent adverse prognostic factors, correlating with adverse mutations (, RAS pathway) and high-risk clinical features. Notably, MLR > 1 identified a subset of patients with dysplastic CMML with molecular and clinical profiles resembling proliferative CMML (MP-CMML). These variables retained their prognostic impact after adjustment for established prognostic models (CMML-specific prognostic scoring system [CPSS], CPSS with the addition of the variable platelet < 100 × 10⁹/L [CPSS-P], and Mayo prognostic model), and their addition improved predictive performance. Based on these and other objective variables readily available from a routine complete blood count (CBC), we developed the objective prognostic index for CMML (OPIC), which integrates hemoglobin < 11 g/dL, platelets < 100 × 10⁹/L, MP-CMML, and MLR > 1. OPIC stratified patients into four risk categories with distinct survival outcomes (median overall survival [OS]: 104, 66.6, 34.3, and 18.3 months), demonstrating strong discriminatory power. Variable selection was performed using stepwise and elastic net regression, and random survival forests. Model performance metrics, including the C-index, time-dependent area under the receiver operating characteristic curve, and the Brier Score, were internally validated using bootstrapping-based resampling methods and externally validated in a cohort of 250 patients. OPIC provides a robust, accessible tool for CMML risk stratification, supporting its integration into routine clinical workflows and early therapeutic decision-making.