Chronic neutrophilic leukemia (CNL) is a rare blood cancer in which the bone marrow makes too many mature neutrophils, the white blood cells that normally fight bacterial infection. It belongs to the myeloproliferative neoplasms, is usually diagnosed in older adults, and is driven in most cases by a mutation in the CSF3R gene. Diagnosis requires a persistently high neutrophil count, a bone marrow biopsy and genetic tests that rule out look-alike conditions such as chronic myeloid leukemia. Treatment ranges from oral medication to control the count through to stem cell transplant for suitable patients.
What Is Chronic Neutrophilic Leukemia?
CNL is one of the rarest hematologic malignancies. It is classed with other chronic myeloid disorders such as polycythemia vera and essential thrombocythemia, where a single abnormal marrow stem cell overproduces one type of blood cell.
In CNL that cell type is the neutrophil. Unlike acute leukemia, the extra cells are mostly mature and look normal under the microscope. Blasts, the very immature cells that dominate acute leukemia, are few in the chronic phase.
Because the cells look mature, CNL can be mistaken for a reaction to infection or inflammation. That is why it is often called a diagnosis of exclusion: other causes of a raised neutrophil count must be ruled out first. For the broader picture of blood cancers, see our leukemia guide.
Causes: The CSF3R Mutation and Other Genes
Neutrophil production is controlled by a hormone called granulocyte colony-stimulating factor (G-CSF). It acts on a receptor encoded by the CSF3R gene. In most people with CNL, an acquired mutation in CSF3R switches the receptor permanently on, so the marrow keeps making neutrophils without any signal to do so.
The most common change is called CSF3R T618I. Mutations near the cell membrane like this one activate the JAK-STAT signaling pathway, which has treatment implications discussed below. Less often, the mutation shortens the receptor’s tail and signals through other pathways.
Other acquired mutations are frequently found alongside CSF3R, most notably SETBP1 and ASXL1. These are associated with a more aggressive course. These mutations are acquired during life in the marrow; CNL is not an inherited disease, and no clear lifestyle or environmental cause has been established.
Signs and Symptoms
Many people have no symptoms at diagnosis, and CNL is found when a routine blood count shows a high white cell count. When symptoms occur, they tend to be vague:
- Fatigue and low energy
- Unintentional weight loss, night sweats or low-grade fevers
- Fullness or discomfort under the left ribs from an enlarged spleen (splenomegaly), sometimes with early satiety
- Easy bruising or bleeding, which can occur even when the platelet count is normal
- Gout or itching in some patients
An enlarged spleen is the most common physical finding. The liver may also be enlarged. Over time the disease can progress, with falling blood counts or transformation to an acute leukemia.
How Chronic Neutrophilic Leukemia Is Diagnosed
Diagnosis combines blood tests, a bone marrow examination and molecular testing. The World Health Organization (WHO) criteria center on the features in the table below.
| Criterion | What doctors look for |
|---|---|
| White cell count | 25 x 10^9/L or higher (normal adult range roughly 4 to 11 x 10^9/L) |
| Neutrophils and bands | At least 80% of white cells |
| Immature granulocytes | Less than 10% of white cells; blasts rarely seen |
| Monocytes | Less than 1 x 10^9/L |
| Cell appearance | No dysplasia (abnormal-looking granulocytes) |
| Bone marrow | Hypercellular with increased neutrophil production; blasts below 5% |
| Genetics | CSF3R mutation present; BCR-ABL1 and other defining myeloid rearrangements absent |
A bone marrow aspirate and biopsy confirm the marrow is packed with neutrophil precursors and show that blasts are not increased. Next-generation sequencing identifies CSF3R and co-mutations such as SETBP1 and ASXL1.
When no CSF3R mutation is found, a diagnosis is still possible if persistent neutrophilia has no other explanation. That requires careful exclusion of infection, inflammatory disease, hidden cancers and certain plasma cell disorders, which can all push neutrophil counts up.
CNL vs CML and Other Look-Alikes
The condition most often confused with CNL is chronic myeloid leukemia. The key difference is genetic: CML carries the BCR-ABL1 fusion (the Philadelphia chromosome), and CNL does not. Our guide to chronic myelogenous leukemia covers that disease in detail.
| Condition | Key blood feature | Distinguishing test |
|---|---|---|
| Chronic neutrophilic leukemia | Mature neutrophils, few immature cells | CSF3R mutation; BCR-ABL1 negative |
| Chronic myeloid leukemia | Full spectrum of immature granulocytes, basophilia | BCR-ABL1 positive |
| Atypical CML | Immature granulocytes and dysplasia | Dysplasia on smear; BCR-ABL1 negative |
| Chronic myelomonocytic leukemia | Raised monocytes | Monocyte count and marrow findings |
| Reactive neutrophilia | Raised neutrophils with an identifiable cause | Resolves when infection or inflammation settles |
Treatment and Management
There is no single standard treatment, because CNL is so rare that large comparative trials have not been possible. Care is individualized and ideally led by a hematologist with experience in myeloproliferative neoplasms.
- Hydroxyurea: an oral medication that is commonly the first choice to lower the white cell count and shrink the spleen.
- Ruxolitinib: a JAK inhibitor that can be effective in patients with membrane-proximal CSF3R mutations such as T618I, which signal through JAK-STAT. It is used off-label or in clinical trials in many countries.
- Interferon alfa: an option in selected patients, including younger people.
- Allogeneic stem cell transplant: the only treatment with curative potential, considered for fit patients, particularly those with high-risk features or progression.
- Supportive care: managing bleeding risk, gout and spleen symptoms.
Removing the spleen is generally avoided, as it can make the neutrophil count rise further. Regular blood counts track response and watch for signs of progression.
Outlook and When to See a Doctor
CNL is a serious chronic cancer, and its course varies widely. Some people remain stable for years on oral therapy, while others progress more quickly, particularly when SETBP1 or ASXL1 mutations are present. Transplant offers the best chance of long-term control for eligible patients.
See a doctor if a blood test shows a persistently high white cell or neutrophil count without an obvious infection, or if you notice left-sided abdominal fullness, unexplained weight loss, night sweats or easy bruising. Seek urgent care for bleeding that will not stop, high fever, or sudden severe abdominal pain.
Frequently Asked Questions
Is chronic neutrophilic leukemia the same as CML?
No. Both raise the white cell count and enlarge the spleen, but CML is caused by the BCR-ABL1 fusion and responds to tyrosine kinase inhibitors such as imatinib. CNL lacks BCR-ABL1 and is usually driven by CSF3R mutations.
Is CNL hereditary?
No. The CSF3R and related mutations arise in bone marrow cells during a person’s lifetime. They are not passed from parent to child.
Can chronic neutrophilic leukemia turn into acute leukemia?
Yes, in some patients. Transformation to acute myeloid leukemia is one of the recognized ways the disease progresses, which is why regular monitoring of blood counts and blasts matters.
Is CNL curable?
An allogeneic stem cell transplant can cure CNL in some people. For those who are not transplant candidates, treatment aims to control counts and symptoms over the long term.
