Chronic neutrophilic leukaemia (CNL) is a very rare myeloproliferative neoplasm (MPN) in which there is a persistent increase in the number of white blood cells in the bone marrow, mainly the mature neutrophil cells. MPNs are chronic disorders where the myeloid stem cells in the bone marrow make too many abnormal red blood cells, white blood cells, or platelets which do not function properly. In CNL, there are too many neutrophil cells. Neutrophil cells protect the body against bacterial infections and inflammation.
To date, only around 200 patients with CNL have been identified. The median age at diagnosis of the patients with CNL in one large study was 73 years, and it is slightly more common in males (60%).
What are the symptoms of chronic neutrophilic leukaemia?
Patients with CNL do not normally present with specific symptoms apart from possible fatigue or easy bruising. Often a routine blood test or medical examination will show an abnormal blood cell count or enlarged liver and/or spleen.
In due course, the excess of neutrophils circulating in the blood will cause signs and symptoms such as:
- Weight loss
- Easy bruising
- Bone pain
- Night sweats
- Enlarged spleen which causes a feeling of fullness below the ribs on the left side
- Enlarged liver
How is CNL diagnosed?
Blood and bone marrow samples are examined to diagnose CNL according to the 2016 WHO classification criteria. The following diagnostic tests are required:
- Blood samples are obtained to measure the complete blood cell count (number and quality of white blood cells, red blood cells and platelets), as well as the types of white blood cells to show which white blood cells are increased.
- Bone marrow biopsy – A small sample of bone marrow is needed to confirm the diagnosis. The bone marrow sample can be taken from the hip bone under local anaesthetic, using special biopsy needles: liquid bone marrow (aspirate) and/or a tiny core of bone marrow tissue (trephine).
- Chromosome analysis to detect common gene mutations linked to CNL such as CSF3R T618I mutations.
CNL diagnostic requirements
The cells from the blood and bone marrow are examined under a microscope by a haematologist (doctor who specialises in diseases of the blood). To make the diagnosis, the 2016 WHO classification criteria for CNL must be fulfilled. These are:
- Peripheral blood white blood cells greater or equal to 25×109/l.
- Segments of, or immature, neutrophils making up 80% or greater of white blood cells
- Immature neutrophils making up less than 10% of white blood cells
- Immature neutrophil myeloid stem cells rarely observed
- Monocyte count less than 1×109/l
- No abnormality in the development of granulocytes in general
- Presence of the CSF3R T618I mutation or other activating CSF3R mutations.
- Hypercellular (many cells present) bone marrow, where the amount of bone marrow cells are increased relative to the amount of bone marrow fat.
- Increased number and percentage of neutrophils
- Maturation of neutrophils appears normal
- Myeloid stem cells make up less than 5% of bone marrow cells which have a nucleus
- The following diagnoses must be excluded:
- Chronic myeloid leukaemia: Positive for the BCR-ABL1 (Breakpoint Cluster Region-Abelson Murine Leukaemia Viral proto-oncogene 1) gene
- Polycythaemia vera (abnormal increase of red blood cells)
- Essential thrombocythaemia (excess production of platelets leading to abnormal blood clotting)
- Primary myelofibrosis (build-up of scar tissue in the bone marrow)
- No rearrangement (exchange of genetic material among genes) for the following genes:
- PDGFRA and PDGFRB (Platelet-Derived Growth Factors Receptors A and B) genes
- FGFR1 (Fibroblast Growth Factor Receptor 1) gene
- PCM1-JAK2 (Peri-Centriolar Material 1-Janus-Activated Kinase 2) gene
- Or, in the absence of a CSFR3R mutation, patients must have:
- Persistent increase in the number of neutrophils for at least three months
- Enlargement of the spleen
- No identifiable cause for an increase in the number of neutrophils, including absence of a plasma cell cancer
- Or, if present, demonstration of genetically identical myeloid cells
The CSF3R T618I mutation represents an accurate and specific marker for the diagnosis of CNL.
Risk of transformation
Transformation to AML is reported to occur in 10% to 20% of patients. Median time to AML transformation of 21 months with a range of three to 94 months.
How is CNL treated?
There is currently no standard of care for CNL. Since the discovery of the CSF3R T618I gene, which established CNL as a distinct clinical leukaemia type, the treatments for the other chronic leukaemias are no longer used in CNL patients. However, given that CNL is very rare, CNL-specific treatments are limited. Current treatment for CNL is based on managing the symptoms, using cytoreductive drugs, which decrease the number of cells in the blood, such as hydroxycarbamide (also known as hydroxyurea) and interferon-alpha (IFN-a).
Some chemotherapy drugs such as thalidomide, cladribine, imatinib and ruxolitinib have also been used but with little success.
New drugs in development
- Since CSF3R gene mutations are present in the majority of patients with CNL, research has concentrated on these mutations for possible new treatments.
- Two types of CSF3R mutations which showed susceptibilities to different drugs in the laboratory have been demonstrated. These mutations are the CSF3R T618I mutation and the truncated CSF3R mutations, which show susceptibilities to ruxolitinib and dasatinib, respectively.
- However, case reports of ruxolitinib in CNL patients have shown mixed results, and the efficacy and safety of dasatinib in patients with CNL are still being studied.
Hydroxycarbamide was previously the most used treatment in patients with CNL as it reduces the white blood cell count and decreases the enlarged spleen, which is caused by the greatly increased numbers of white blood cells.
After initial efficacy with hydroxycarbamide, most CNL patients tend to become refractory (i.e. stopped responding to their treatment).
IFN-a is a known immunotherapy, which boosts the body’s natural immune system to fight the leukaemia. Specifically, it reduces the rate at which blood cells are made in the bone marrow IFN-a is the only treatment which has been shown to give durable remission in CNL patients. A review of 14 cases of patients with CNL featured a patient who achieved clinical remission for 41 months while being treated with IFN-a. However, in another case report, one patient with CNL achieved only partial response for at least two years when receiving IFN-a in combination with hydroxycarbamide, but then suffered progression of the CNL.
Chemotherapy is the use of drugs that prevent the ability of cancer cells to grow and divide, thereby destroying the cancer cells over time. Targeted therapy is a treatment that targets specific genes or proteins of leukaemia cells.
In the search for new targeted chemotherapies for the treatment of CNL, efforts have concentrated on the CSF3R mutations:
- CSF3R T618I mutation, situated close to the membrane of the cell, activates the JAK enzyme protein and is therefore susceptible to the JAK inhibitor, ruxolitinib.
- Truncated CSF3R mutations, where the gene is shortened or truncated, are situated in the middle of the cell and activate SRC kinases. These mutations exhibit drug sensitivity to SRC kinase inhibitors, such as dasatinib.
Stem cell transplant
While it theoretically represents the only chance of a cure, few case reports of allogeneic stem cell transplantation (allo-SCT) in patients with CNL are available. Nevertheless, because of the possibility of the evolution of CNL into acute myeloid leukaemia (AML) and the number of cases of CNL that become refractory, allo-SCT can be used for certain patients. An allo-SCT is the receipt of blood forming stem cells from a genetically similar, but not identical, donor.
Despite no firm evidence being available, it appears that allo-SCT is best performed in the chronic phase of CNL. Therefore, it may be prudent to have patients evaluated for allo-SCT early in their disease and certainly before the blast transformation stage.
Surgical removal of the spleen
Surgical removal of the spleen may be recommended for some patients to relieve symptoms of abdominal pain. A surgical oncologist who is a doctor specialising in cancer surgery will usually perform this procedure. Removal of the spleen, however, caused an increase in neutrophils and is only really used as a palliative measure. Splenic irradiation (use of high energy radiation from X-rays, gamma rays, or neutrons to kill cancer cells and shrink tumours) can be used to decrease abdominal pain caused by the enlarged spleen.
Questions to ask your medical team about CNL
We understand going through a blood cancer through journey can be difficult. It may help to talk to a close friend or relative about how you are feeling. Here are some questions that may be useful to ask your doctor.
- How would I know if I had CNL?
- What tests will I need to have?
- What will the tests show?
- How long will the results take?
- How rare is CNL?
- What sort of treatment will I need?
- How long will my treatment last?
- What will the side effects be?
- Is there anything I should or shouldn’t eat?
- Will I be able to go back to work?
- Where can I get help with claiming benefits and grants?
- Where can I get help dealing with my feelings?
We have free patient information available for CNL patients.
You can download the booklets on our information pages here.
Alternatively, you can have the information delivered free of charge by requesting it through our resources page.
Published: September 2020
Review date: July 2023