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Objective: To explore the prognostic impact of hypomethylating agents (HMA) versus hydroxyurea plus best supportive care (HU/BSC) in patients with intermediate-and high-risk chronic myelomonocytic leukemia (CMML), and to analyze the patterns of clonal evolution and dynamic changes of inflammatory cytokines in patients with disease progression before and after HMA treatment. Methods: A total of 63 patients diagnosed with intermediate-and high-risk CMML admitted to the Department of Hematology, the Second Hospital of Tianjin Medical University between October 20 2017 and May 8 2025 were retrospectively enrolled. All patients were followed up every 3 months via outpatient and inpatient visits after discharge, with the last follow-up conducted on February 28, 2026. According to treatment regimens, the patients were divided into HMA group (n=31) and HU/BSC group (n=32). Treatment response, disease progression and survival outcomes were compared between the 2 groups. The Kaplan-Meier method was used to plot the survival curves of overall survival (OS) and progression-free survival (PFS). Bone marrow DNA was collected from patients with disease progression before and after treatment with HMA (n=20) and HU/BSC (n=13). Next-generation sequencing was used to detect 325 mutated genes related to hematological malignancies, and the clonal evolution of gene mutations in patients receiving the 2 treatment regimens before and after disease progression was investigated. Bone marrow supernatant specimens were collected from patients with disease progression treated with HMAs (n=8) and HU/BSC (n=8), and enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of 21 inflammatory cytokines including IL-6 and IFN-γ. The differences in inflammatory cytokine expression before and after disease progression were compared. Results: The median follow-up duration for all patients [M(Q₁,Q₃)] was 21 (10, 40) months. The median OS was 22.0 months (95%CI: 11.8-32.2) in the HMA group and 36.0 months (95%CI: 23.6-48.4) in the HU/BSC group, with no statistically significant difference between groups (P=0.208). The median PFS was 18.0 months (95%CI: 10.8-25.2) and 26.0 months (95%CI: 19.9-21.1) respectively, and the difference was also not statistically significant (P=0.108). Among patients with disease progression after HMA treatment, newly acquired mutations were predominantly enriched in RAS pathway genes, accounting for 25% (5/20). Clonal expansion of SF3B1, TP53 and RUNX1 was observed, and the mutational burden of each gene accounted for 10% (2/20). Compared with baseline levels, the concentrations of TNF-α [113.6 (104.1, 147.1) pg/ml vs 25.7 (20.2, 41.3) pg/ml, P<0.001] and IL-8 [77.5 (54.6, 115.8) pg/ml vs 7.0 (2.6, 9.2) pg/ml, P=0.003] were significantly increased after disease progression, while the level of IFN-γ [341.5 (221.2, 460.7) pg/ml vs 732.7 (389.0, 852.4) pg/ml, P=0.013] was markedly decreased. Conclusions: Compared with HU/BSC regimen, HMA failed to significantly improve OS and PFS in patients with intermediate-and high-risk CMML. Disease progression after HMA treatment may be closely associated with newly emerging mutations in the RAS pathway, clonal expansion of pre-existing mutations such as TP53, as well as the upregulation of TNF-α and IL-8 and downregulation of IFN-γ.