To date, approximately only 200 patients have been identified. The median age of the patients was 65 years at diagnosis, and 67% were male.
CNL is characterised by the following:
- Continued production of mature neutrophils (which is not being caused by anything else)
- Bone marrow white blood cell hyperplasia (enlargement of an organ/tissue due to an increase in the rate of reproduction of its cells)
- Hepatosplenomegaly (enlarged liver and spleen)
CNL may stay the same for many years or it may progress quickly to acute leukaemia, only to acute myeloid leukaemia (AML) so far.Patients’ risk factors, which will determine their likely outcome are evaluated individually by your doctor.
Signs and symptoms of CNL
Patients with CNL do not normally present with specific symptoms apart from maybe fatigue or easy bruising. Often a routine blood test or medical exam will show an abnormal blood cell count or enlarged liver and/or spleen.
In due course, the excess of neutrophils circulating in the peripheral blood will cause symptoms such as:
- Weight loss
- Easy bruising
- Bone pain
- Night sweats
- Enlarged spleen (causing a feeling of fullness below the ribs on the left side)
- Enlarged liver
According to the 2008 WHO classification system for tumours of the haematopoietic and lymphoid tissues, the diagnostic criteria for CNL were:
- White cell count greater than 25 ×109/l
- More than 80% of mature neutrophils
- Less than 10% of immature neutrophils
- Absence of the following conditions:
- Granulocytic dysplasia (abnormal growth of white blood cells called granulocytes)
- Myelodysplasia in other cells in the bone marrow other than granulocytes
- Monocytosis (increased levels of monocytes which are white blood cells that become scavenger cells to clear infection in the immune system)
- Eosinophilia (increased levels of eosinophils which are white blood cells that have a protective immunity role against parasites and allergens)
- Basophilia (increased levels of basophils which are white blood cells that are responsible inflammatory reactions during an immune response)
In 2013, the discovery of the T618I mutation of CSF3Rgene (colony-stimulating factor 3 receptor) in over 80% of CNL patients has greatly clarified the field of research in CNL. This CSF3RT618I mutation represents a biomarker for diagnosis. The new edition of the 2016 World Health Organization (WHO) classification system for tumours of the hematopoietic and lymphoid tissues, now includes the CSF3RT618I mutation in its diagnostic criteria for CNL.
While CSF3RT618I mutations occur in more than 80% of patients with CNL, they do not occur in some 20% of CNL patients, and these mutations are also known to occur in patients with atypical CML. Consequently, the WHO diagnosis 2016 also requires the exclusion other causes of neutrophilia, including infections and inflammatory processes, metastatic cancer, and plasma cell cancers with secondary neutrophilia. Demonstration of the absence of the BCR-ABL1 mutation, PDGFRA, PDGFRB, or FGFR1, or PCM1-JAK2 rearrangements helps exclude atypical Chronic myeloid leukaemia (CML) and chronic eosinophilic leukaemia (Table 1).
Several recent studies have found other mutations in CNL patients, including JAK2 (Janus Kinase 2), CALR(Calreticulin), ASXL1 (Additional sex combs-like 1) and SETBP1 (SET binding protein 1) mutations. Further research is needed to determine whether these mutations can serve as prognostic markers that will help guide doctors making treatment decisions.
The diagnosis of CNL requires a number of investigations to be able to apply the 2016 WHO diagnostic criteria for CNL.
- Blood samples to measure the complete blood cell counts (number and quality of white blood cells, red blood cells and platelets)
- Bone marrow biopsies: samples of bone marrow cells are obtained by bone marrow aspiration.
The cells from the blood and marrow samples are examined under a microscope by a haematologist (doctor who specialises in diseases of the blood). To achieve a definite diagnosis, the bone marrow will be examined for the following:
- Cell genetic abnormalities
- Karyotyping: This evaluates the number and structure of the chromosomes to identify any abnormalities.
- Polymerase chain reaction test: This test is occasionally performed to determine certain changes in the structure or function of genes.
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.
Treatment of CNL
Prior to the discovery of the CSF3RT618I gene, there were no specific treatments for CNL because of the rarity of the disease and the consequent lack of clinical trials. Management choices from other types of chronic leukaemia have been tried, but without achieving any improvements. Therapy options were therefore initially targeted at managing the symptoms.
Other treatments included cytoreductive drugs (drugs to decrease the size of the tumour) such as oral hydroxycarbamide (also known as hydroxyurea), and interferon-alpha (IFN-a) to control the growth of cancer cells. IFN-a is a known immunotherapy, which consists of purified derivative from fractions of white blood cells from the blood. Immunotherapy acts by boosting the body’s natural immune system to fight the leukaemia.
Drugs that have been used in the treatment of patients include interferon, thalidomide, cladribine, imatinib and ruxolitinib. Those which have shown most promise are shown below.
IFN-a is the only treatment which has been shown to give durable remissions in CNL as shown in a number of reports.
Chemotherapy is the use of drugs to prevent the ability of cancer cells to grow and divide, thereby destroying the cancer cells overtime. Targeted therapy is a treatment that targets the specific genes or proteins of leukaemia cells, as is the case for ruxolitinib.
Ruxolitinib is a JAK inhibitor which is currently indicated for the treatment of patients with polycythaemia vera and myelofibrosis (serious cancer characterised by bone marrow fibrosis). It has shown promise for CNL and atypical CML.
To further clarify the role of ruxolitinib in CNL patients with varying mutations, a multicentre phase 2 clinical trial (NCT02092324) is currently in progress to determine the proportion of patients with CNL and aCML who respond to ruxolitinib. The study started on 5 May 2014 and is due to be completed in April 2019. Further details of the trial can be seen at https://clinicaltrials.gov/ct2/show/NCT02092324?term=NCT02092324&rank=1.
Standard induction therapy with anthracycline and cytarabine in the accelerated or blast phases of CNL has failed to achieve lasting remission.
Other therapies have included drugs such as hypomethylating agents (four patients), thalidomide (two patients), cladribine (two patients) and imatinib (one patient). However, none of these treatments have enabled patients to achieve remission.
Stem cell transplant
Because of the possibility of progression to blast transformation and the number of cases that become refractory, allogeneic stem cell transplantation (ASCT) has been used for a number of patients. An ASCT is the receipt of blood forming stem cells from a genetically similar, but not identical, donor. At present, ASCT is the only known curative option for patients.
Results from other series have confirmed that patients receiving ASCT in the blast or accelerated phases appear to experience worse outcomes with regards to toxicity and/or early relapse.
Despite no firm evidence, it appears that ASCT is best performed in the chronic phase of CNL. Therefore, it may be prudent to have patients evaluated for ASCT early in their disease and certainly before the blast transformation stage.
Supportive or palliative care is medical care that relieves symptoms without dealing with the cause of the condition.
Hydroxycarbamide has previously been the most used treatment in patients with CNL as it reduces the white blood cell count and the splenomegaly, which is caused by the greatly increased numbers of white blood cells.
A splenectomy, which is an operation to remove the spleen may be recommended for some patients to relieve symptoms of abdominal pain.