# Chronic neutrophilic leukemia
**Chronic neutrophilic leukemia** (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm, a bone marrow cancer defined by persistent, predominantly mature neutrophilic leukocytosis (abnormally high white blood cell count), granulocyte hyperplasia of the bone marrow, and frequent hepatosplenomegaly.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) Its molecular hallmark is an activating mutation in CSF3R, the gene encoding the receptor for colony-stimulating factor 3 (granulocyte colony-stimulating factor), which the World Health Organization incorporated into the formal diagnostic criteria in 2016.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/)
| Key fact | Detail |
|---|---|
| Disease class | Rare BCR::ABL1-negative myeloproliferative neoplasm with sustained mature neutrophil proliferation, marrow granulocytic hyperplasia, and hepatosplenomegaly[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) |
| Incidence | Approximately 0.1 cases per 1,000,000 people, with a slight male predominance[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
| Age and sex | Median age at diagnosis 71 years (range 33–92.5) in the two largest series[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
| Driver mutation | Activating CSF3R mutation, classically T618I, documented in more than 80% of cases[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
| WHO 2022 blood criteria | Leukocytosis ≥25 × 109/L; segmented neutrophils plus bands ≥80% of white cells; neutrophil precursors <10%; no dysgranulopoiesis[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
| Prognosis | Overall survival 15–31 months; leukemic transformation to acute myeloid leukemia in roughly 10–25% of patients[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
| Treatment | No standard of care; hydroxyurea, interferon, JAK inhibitors, and hypomethylating agents are used without disease modification; allogeneic hematopoietic stem cell transplant is the only potentially curative modality[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) |
## History and recognition
The earliest account is a 1920 report by Tuohy describing a 58-year-old woman with splenomegaly and an overwhelming preponderance of mature polymorphonuclear neutrophils.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) Emil-Weil and See reported further possible cases in 1932, and the term "chronic neutrophilic leukemia" was introduced by Tanzer and colleagues in *The Lancet* in 1964.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) Whether these early reports represent true CNL is uncertain, because diagnostic criteria did not exist and many historical cases were probably reactive neutrophilia or other myeloid malignancies mislabeled as CNL.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/)
**Formal classification came late.** The first operational diagnostic criteria, proposed by You and Weisbrot in 1979, relied on sustained mature neutrophilic leukocytosis, hepatosplenomegaly, absence of a leukemoid reaction, and elevated leukocyte alkaline phosphatase, serum vitamin B12, and uric acid.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) The WHO Classification of Neoplastic Diseases first acknowledged CNL as a distinct myeloproliferative malignancy in 2001.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/) Recorded cases grew from 13 by 1979, to fewer than 100 by 1996, to 129 by 2002 and 150 by 2005; more than 200 are now recorded, although the true occurrence is likely lower once strict WHO criteria are applied.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/)
## Clinical and laboratory features
CNL commonly presents as incidental neutrophilic leukocytosis. In a series of 14 molecularly defined patients, 71% had antecedent chronic leukocytosis lasting a median of 12.5 months (range 5–84 months).[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Symptoms may include fatigue, constitutional symptoms, bone pain, pruritus, easy bruising, or gout; examination reveals splenomegaly in up to 67% of patients and sometimes hepatomegaly, while lymph node involvement is uncommon.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
The blood film shows persistent mature neutrophilia, with segmented neutrophils and bands forming at least 80% of white cells and few or no circulating immature myeloid precursors, and an absence of monocytosis, basophilia, and eosinophilia.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) In a 2023 series of 24 WHO-defined cases, median values at diagnosis were hemoglobin 7.98 g/dL, leukocyte count 52.7 × 109/L, platelets 260 × 109/L, and neutrophils 48 × 109/L.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Mild to moderate anemia is common, and the leukocyte alkaline phosphatase score is typically elevated, in contrast to the low score seen in chronic myeloid leukemia; vitamin B12 levels are frequently high from transcobalamin release by granulocytes.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
**Bone marrow findings** include hypercellularity exceeding 90% due to increased neutrophilic granulopoiesis, a myeloid to erythroid ratio that may exceed 20:1, fewer than 5% blasts, and usually no dysplasia; reticulin fibrosis is typically normal or grade 1 at most.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) [Cytogenetics](https://www.edgepedia.org/cytogenetics) are normal in approximately 90% of cases, so conventional chromosome analysis does not separate CNL from nonmalignant neutrophilia.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC5266507/)
## Molecular biology
Before 2013 no molecular marker could prove clonality in CNL, which had been diagnosed largely by exclusion.[4](https://haematologica.org/article/view/7230) That year, deep sequencing of patients with CNL or [atypical chronic myeloid leukemia](https://www.edgepedia.org/atypical-chronic-myeloid-leukemia) identified activating CSF3R mutations in 16 of 27 patients (59%).[5](https://www.nejm.org/doi/full/10.1056/NEJMoa1214514) The mutations fall into two regions of the receptor with different downstream signaling: truncation mutations activate SRC family–TNK2 kinase signaling and show sensitivity to dasatinib, while membrane-proximal mutations preferentially activate JAK signaling.[5](https://www.nejm.org/doi/full/10.1056/NEJMoa1214514) A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement on the JAK1/2 inhibitor ruxolitinib.[5](https://www.nejm.org/doi/full/10.1056/NEJMoa1214514)
The classically described mutation is CSF3R T618I, present in more than 80% of cases.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Additional lesions modify the phenotype: SETBP1 and ASXL1 mutations occur at high frequency in CNL and atypical CML and carry prognostic value, with patients carrying SETBP1 and/or ASXL1 mutations having a worse prognosis.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC5266507/) Germline CSF3R variants also exist: a CSF3R T618I mutation has been documented as inherited across a four-generation family with several members presenting with CNL, and a germline T618I case with no ASXL1, SETBP1, or TET2 mutations showed stable leukocytosis over 11 years, suggesting that additional mutational hits are required for full CNL progression.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC11763460/) • [7](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.27321) In preclinical work, both proximal and compound CSF3R mutations relied on enhanced MAPK signaling for oncogenic transformation, and targeting Mek1/2 with trametinib abrogated leukemia development in mice carrying these variants.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/)
## Diagnosis and differential diagnosis
The 2022 WHO criteria require peripheral blood leukocytosis of at least 25 × 109/L, segmented neutrophils plus band forms comprising at least 80% of white cells, neutrophil precursors below 10%, monocytes below 10%, absence of dysgranulopoiesis, a hypercellular marrow with increased neutrophil granulocytes and fewer than 5% blasts, exclusion of BCR::ABL1-positive chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis, no [PDGFRA](https://www.edgepedia.org/pdgfra), PDGFRB, or FGFR1 rearrangement or PCM1::JAK2 fusion, and the presence of CSF3R T618I or another activating CSF3R mutation.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) The WHO also recognizes CSF3R-negative disease when supported by persistent neutrophilia of at least 3 months, splenomegaly, and no identifiable reactive cause, including absence of a plasma cell neoplasm.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) The 2022 International Consensus Classification is broadly consistent with the WHO but lowers the leukocytosis threshold to ≥13 × 109/L in cases carrying an activating CSF3R mutation, keeping the 25 × 109/L threshold for those lacking one.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
**Distinguishing CNL from its mimickers** drives the diagnostic workup. Reactive neutrophilia and leukemoid reactions can produce marked neutrophilia with normal cytogenetics and no BCR::ABL1 fusion, so clonality must be demonstrated, usually by identifying a CSF3R mutation.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) The closest differential is atypical chronic myeloid leukemia (aCML), classified as MDS/MPN with neutrophilia in the 2022 WHO scheme: aCML shows dysgranulopoiesis and circulating immature myeloid cells comprising at least 10% of white cells, versus fewer than 10% in CNL.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) CSF3R mutations cannot by themselves separate the two diagnoses, because several aCML cases also harbor them.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC9048254/) [Chronic myelomonocytic leukemia](https://www.edgepedia.org/chronic-myelomonocytic-leukemia) is distinguished by persistent absolute monocytosis and dysplasia.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC9048254/) Rarely, ectopic production of G-CSF by solid tumors, reported with urological, lung, mesothelial, thyroid, and sarcoma malignancies among others, produces paraneoplastic neutrophilic leukocytosis that mimics CNL.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
## Prognosis
CNL is an often aggressive disease with a poor prognosis; most patients die of disease complications or transform to acute myeloid leukemia.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC9048254/) Reported overall survival is 15–31 months, and leukemic transformation occurs in roughly 10–25% of patients, with a median time to AML transformation of 15–21 months.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Progression to polycythemia vera or chronic myelomonocytic leukemia occurs less commonly.[7](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.27321) The Mayo Clinic risk model for CNL assigns 2 points for platelets below 160 × 109/L, 1 point for leukocytes above 60 × 109/L, and 1 point for an ASXL1 mutation, separating low-risk (0–1 points) from high-risk (2–4 points) patients.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Worsening anemia or thrombocytopenia, increasing leukocytosis, and growing splenomegaly often herald progression or blast crisis.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
## Management
Management is risk-driven and symptom-directed, with no current standard of care.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) The most commonly used agents are hydroxyurea, interferon, [Janus kinase](https://www.edgepedia.org/janus-kinase) inhibitors, and hypomethylating agents, though none are disease-modifying.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) Allogeneic hematopoietic stem cell transplant is the only potentially curative modality and should be considered in eligible patients; persistence of molecular markers after transplant is associated with increased relapse risk.[2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC5266507/) The discovery of differential kinase signaling underlies targeted approaches: the CSF3R mutation classes show differential sensitivity to tyrosine kinase inhibitors in preclinical models, and [fedratinib](https://www.edgepedia.org/fedratinib) has been evaluated in a phase 2 study.[5](https://www.nejm.org/doi/full/10.1056/NEJMoa1214514) • [2](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
## References
1. [Chronic neutrophilic leukemia: new science and new diagnostic criteria, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5811432/)
2. [Szuber N, Orazi A, Tefferi A, et al. Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management. American Journal of Hematology](https://onlinelibrary.wiley.com/doi/10.1002/ajh.27321?af=R)
3. [What's different about atypical CML and chronic neutrophilic leukemia? PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5266507/)
4. [Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica](https://haematologica.org/article/view/7230)
5. [Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML. New England Journal of Medicine](https://www.nejm.org/doi/full/10.1056/NEJMoa1214514)
6. [Chronic Neutrophilic Leukemia: Advances in Diagnosis, Genetic Insights, and Management Strategies, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11763460/)
7. [Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update (PDF direct link)](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.27321)
8. [Chronic Neutrophilic Leukemia: A Comprehensive Review of Clinical Characteristics, Genetic Landscape and Management, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9048254/)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Cardiovascular and blood conditions › Blood disorders (hematologic conditions) › Leukemias › Other and rarer leukemia subtypes › Atypical and rare myeloproliferative leukemias*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 11, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license