Integrated Clinical, Cytogenetic and Molecular Profiling in Chronic Myelomonocytic Leukemia: Genotype–Phenotype Associations and Risk- Model Discordance in an Indian Cohort.

Background Chronic myelomonocytic leukemia (CMML) is a biologically heterogeneous myeloid neoplasm. Cytogenetic and molecular alterations are increasingly used for disease characterization and risk assessment. Indian data integrating molecular findings with clinical parameters and prognostic models remain limited. Methods We retrospectively analyzed 29 patients with newly diagnosed CMML evaluated between May 2021 and December 2025. Baseline clinical, cytogenetic, and molecular data were retrieved at the time of diagnosis. Mutations were characterized by gene frequency, functional pathway category, co-mutation pattern, and genotype–phenotype association across CMML subtypes. Baseline risk assignment and risk-class redistribution were evaluated using conventional and molecularly integrated CMML prognostic models. Results Median age was 65 years (IQR, 57–74 years), and 72.4% of patients were male. CMML-1 accounted for 75.9% of cases, and 62.1% had MP-CMML. Among cytogenetically evaluable cases, a normal karyotype was observed in 71.4%. The most commonly mutated genes were TET2 (58.6%), SRSF2 (44.8%), ASXL1 (34.5%), RUNX1 (27.6%), KRAS (24.1%), and NRAS (20.7%). Epigenetic regulator and signaling pathway alterations were observed in 89.7% and 69.0% of cases, respectively. In exploratory co-mutation analysis, TET2 - SRSF2 was the most frequently observed co-mutation pair, and KRAS mutations clustered in MP-CMML in exploratory analysis. Baseline risk assignment varied considerably across prognostic models. Conclusion Integrated clinicogenomic profiling delineates substantial biological heterogeneity in CMML and model-dependent variation in baseline CMML risk assignment in this Indian cohort.