Chronic Neutrophilic Leukemia: Updated Diagnostic Criteria and Clinical Insights
Understanding Chronic Neutrophilic Leukemia (CNL)
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm characterized by the sustained proliferation of mature neutrophils. With the release of the revised 2016 World Health Organization (WHO) classification of myeloid malignancies and acute leukemias, diagnostic criteria for CNL have been refined to improve accuracy and clinical relevance. These updates emphasize both hematological findings and molecular markers to ensure a precise diagnosis.
Key Hematological Diagnostic Criteria
Elevated White Blood Cell Count with Neutrophil Predominance
One of the hallmark features of CNL is a peripheral blood white cell count exceeding 25 × 10⁹/L. More than 80% of these cells are mature neutrophils, including segmented and band forms. Notably, immature granulocytes—such as promyelocytes and myelocytes—should constitute less than 10% of the total white blood cell count. Blast cells are typically absent or extremely rare, and monocyte counts remain below 0.1 × 10⁹/L, helping to differentiate CNL from other myeloid disorders like chronic myelomonocytic leukemia (CMML).
Normal Myeloid Maturation in Bone Marrow
Bone marrow examination reveals hypercellularity due to granulocytic proliferation, with increased numbers and proportions of neutrophils at all stages of maturation. However, unlike in acute or pre-leukemic conditions, there is no significant dysplasia in the granulocytic lineage. The blast percentage in the bone marrow remains under 5%, which is crucial for ruling out transformation to acute myeloid leukemia. Granulocyte maturation follows a normal pattern, further supporting the diagnosis of a chronic, non-dysplastic process.
Molecular and Genetic Exclusions
A critical component of diagnosing CNL involves excluding other myeloid neoplasms with overlapping features. Patients must not harbor rearrangements in PDGFRα, PDGFRβ, FGFR1, or PCM1-JAK2 fusion genes, as these are associated with distinct, often tyrosine kinase-driven disorders that respond to targeted therapies such as imatinib.
Role of CSF3R Mutation
The presence of a CSF3R (colony-stimulating factor 3 receptor) mutation is a supportive criterion in CNL and is detected in the majority of cases. This mutation promotes constitutive activation of the granulocyte colony-stimulating factor pathway, leading to uncontrolled neutrophil production. When the CSF3R mutation is absent, clinicians must rely on additional clinical evidence: persistent neutrophilia lasting more than three months, confirmed splenomegaly, and exclusion of reactive causes such as infection, inflammatory conditions, or underlying malignancies including plasma cell disorders.
Clinical Implications and Diagnostic Workflow
Diagnosing CNL requires a multidisciplinary approach combining peripheral blood analysis, bone marrow morphology, cytogenetic studies, and molecular testing. Early and accurate identification helps avoid misclassification and ensures appropriate management. Given its rarity, suspected cases should be referred to specialized hematologic centers for comprehensive evaluation, including next-generation sequencing panels to detect CSF3R and other relevant mutations.
Why Accurate Diagnosis Matters
Misdiagnosis can lead to inappropriate treatment, especially since some mimics of CNL respond well to tyrosine kinase inhibitors. Therefore, strict adherence to the updated WHO criteria enhances patient outcomes by guiding targeted testing and therapy. Ongoing research continues to explore the prognostic significance of genetic subtypes within CNL, paving the way for personalized treatment strategies in the future.