Chronic Myelomonocytic Leukemia with CSF3R T618 mutation in an Arab male: a case report

The CSF3R T618I mutation is a highly sensitive and specific molecular marker for Chronic Neutrophilic Leukemia (CNL), present in over 80% of cases. Its occurrence in Chronic Myelomonocytic Leukemia (CMML) is exceedingly rare (< 1% of cases) and poses a significant diagnostic challenge. Accurate classification requires integration of peripheral blood morphology, bone marrow histopathology, flow cytometry, and molecular genetics. A 71-year-old Arab male presented with progressive fatigue, weakness, and unintentional weight loss over one month. Clinical examination revealed pallor and an incidental thyroid nodule, without lymphadenopathy or splenomegaly. Laboratory investigations showed marked leukocytosis (102 × 10⁹/L) with 70% neutrophils and, critically, 15% monocytes (absolute count 15.3 × 10⁹/L), meeting both absolute and relative monocytosis thresholds required by the WHO 2022 criteria for CMML. Serial complete blood counts over three months confirmed persistence of monocytosis. Peripheral blood flow cytometry demonstrated that ≥94% of monocytes were classical (CD14⁺/CD16⁻), a supportive diagnostic criterion for CMML. Bone marrow biopsy was hypercellular (85%) with trilineage dysplasia, myeloid hyperplasia (myeloid:erythroid ratio 8:1), and 7% blasts. Karyotype revealed a balanced Robertsonian translocation t(13;14)(q10;q10) in all cells, likely constitutional. Molecular studies were negative for BCR::ABL1, JAK2, CALR, and MPL, but positive for the CSF3R T618I mutation (variant allele frequency approximately 42% by Sanger sequencing). A diagnosis of CMML-1 (myeloproliferative subtype) with a rare CSF3R mutation was established. The patient was started on hydroxyurea with a good clinical and hematologic response maintained at 6 months of follow-up. This case illustrates that the CSF3R T618I mutation, although strongly associated with CNL, can rarely occur in CMML when strict diagnostic criteria (including persistent relative monocytosis ≥10%) are met. The presence of this mutation in CMML defines a proliferative subtype with a poor prognosis. Reporting such rare cases from underrepresented populations expands the known phenotypic spectrum of CSF3R-mutated myeloid neoplasms and reinforces the principle that molecular markers must be interpreted within the complete clinicopathological context. Comprehensive diagnostics—including flow cytometry and, when available, next-generation sequencing for ASXL1, TET2, SRSF2, and other recurrent mutations—are essential for accurate classification and prognostication.