Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). It is characterized by monocytosis (>0.5 × 10⁹/L) and an increased risk of leukemic transformation (15–20% over 3–5 years). Diagnosis requires sustained monocytosis, consistent bone marrow (BM) morphology, <20% BM or peripheral blood (PB) blasts, and clonal evidence. Cytogenetic abnormalities occur in ~30% of patients, while ~95% have somatic mutations, including TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and RAS pathway (~30%). ASXL1 and DNMT3A mutations negatively impact survival, while TET2 mutations are favorable. Risk stratification includes the Mayo Molecular Model (MMM), which categorizes patients into four risk groups based on factors like ASXL1 mutations, monocyte count, hemoglobin, and platelet count. CMML is classified as either MP-CMML or MD-CMML based on white blood cell count. Treatment options include allogeneic stem cell transplant (ASCT) for high/intermediate-2 risk patients, while drug therapy (e.g., hydroxyurea, hypomethylating agents) is not disease-modifying. A phase-3 study (DACOTA) showed similar survival between decitabine and hydroxyurea in high-risk MP-CMML. CMML is associated with systemic inflammatory autoimmune diseases, leukemia cutis, and lysozyme-induced nephropathy (LyN). LyN is a potential indication for cytoreductive therapy. CMML-specific prognostic models, such as the Mayo Molecular Model (MMM) and the CMML-specific prognostic scoring system (CPSS), help determine risk categories. The MMM includes factors like ASXL1 mutations, monocyte count, and circulating immature myeloid cells, with median survivals of 16, 31, 59, and 97 months for high, intermediate-2, intermediate-1, and low risk groups, respectively. Post-transformation (CMML-BT) has a poor prognosis, with median survival of 6 months and 5-year survival rates of 25%, 9%, and 6%. Treatment options include allogeneic hematopoietic stem cell transplantation (HSCT), but outcomes are generally poor. CMML-specific response criteria, including total symptom score (TSS), are used to assess treatment efficacy. Hypomethylating agents (HMA) like 5-azacitidine and decitabine are the only FDA-approved treatments for CMChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). It is characterized by monocytosis (>0.5 × 10⁹/L) and an increased risk of leukemic transformation (15–20% over 3–5 years). Diagnosis requires sustained monocytosis, consistent bone marrow (BM) morphology, <20% BM or peripheral blood (PB) blasts, and clonal evidence. Cytogenetic abnormalities occur in ~30% of patients, while ~95% have somatic mutations, including TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and RAS pathway (~30%). ASXL1 and DNMT3A mutations negatively impact survival, while TET2 mutations are favorable. Risk stratification includes the Mayo Molecular Model (MMM), which categorizes patients into four risk groups based on factors like ASXL1 mutations, monocyte count, hemoglobin, and platelet count. CMML is classified as either MP-CMML or MD-CMML based on white blood cell count. Treatment options include allogeneic stem cell transplant (ASCT) for high/intermediate-2 risk patients, while drug therapy (e.g., hydroxyurea, hypomethylating agents) is not disease-modifying. A phase-3 study (DACOTA) showed similar survival between decitabine and hydroxyurea in high-risk MP-CMML. CMML is associated with systemic inflammatory autoimmune diseases, leukemia cutis, and lysozyme-induced nephropathy (LyN). LyN is a potential indication for cytoreductive therapy. CMML-specific prognostic models, such as the Mayo Molecular Model (MMM) and the CMML-specific prognostic scoring system (CPSS), help determine risk categories. The MMM includes factors like ASXL1 mutations, monocyte count, and circulating immature myeloid cells, with median survivals of 16, 31, 59, and 97 months for high, intermediate-2, intermediate-1, and low risk groups, respectively. Post-transformation (CMML-BT) has a poor prognosis, with median survival of 6 months and 5-year survival rates of 25%, 9%, and 6%. Treatment options include allogeneic hematopoietic stem cell transplantation (HSCT), but outcomes are generally poor. CMML-specific response criteria, including total symptom score (TSS), are used to assess treatment efficacy. Hypomethylating agents (HMA) like 5-azacitidine and decitabine are the only FDA-approved treatments for CM