Chronic Eosinophilic Leukaemia – Not Otherwise Specified (CEL-NOS)

The exact cause of CEL-NOS is unknown. It has not been linked with any specific chromosome abnormality or gene mutation. Rarely, CEL-NOS may be due to a genetic mutation resulting from environmental factors, smoking or chemical/radiation exposure. However, for most patients, no specific cause can be found. Patients with CEL-NOS do not have the Philadelphia chromosome BCR-ABL fusion gene or other genetically defined entities such as PDGFRα (Platelet-derived growth factor receptors-alpha), PDGFRβ (Platelet-derived growth factor receptors-beta), or FGFR1 (Fibroblast growth factor receptor 1) abnormalities.

In around 10% of patients who do not have any signs or symptoms, CEL-NOS is diagnosed by chance during a routine blood test. However, other patients can experience severe symptoms and signs of cardiovascular or neurological complications due to organ damage brought about by the high eosinophil levels.

Patients with CEL-NOS may experience the following symptoms:

• Fever
• Itching
• Diarrhoea
• Night sweats
• Unexplained weight loss
• Unexplained shortness of breath
• Cough
• Swollen lymph nodes (small swellings in the lymphatic system where lymph is filtered, and lymphocytes are formed. They are part of the immune system)
• Muscle pains
• Anaemia (low level of red blood cells and haemoglobin which is carried by the red blood cells)
• Decreased level of platelets, which are small blood cells that help the body form clots to stop bleeding
• Mucosal ulceration
• Fibrosing of the inside lining of the heart
• Enlarged spleen

The most severe cases of CEL-NOS are mainly due to either tissue damage, particularly thickening and scarring of the heart, or transformation to acute myeloid leukaemia (AML) in patients who have a high level of myeloblast cells.

In patients with hyper-eosinophilia, the first step is to exclude any secondary causes of eosinophilia, such as allergies, infections, medications, autoimmune disorders and/or cancers.

Diagnostic tests

Blood and bone marrow samples are examined to reach a diagnosis of CEL-NOS according to the 2016 WHO classification criteria. The following diagnostic tests are required:

Blood sample: Blood is obtained to measure the complete blood cell count (number and quality of white blood cells, red blood cells and platelets), as well as white blood cell differentiation to show which white blood cells are increased.

Bone marrow biopsy: A sample of bone marrow is taken and the cells from the blood and bone marrow are examined under the microscope by specialists.

Chromosome and gene analysis: These are used to exclude bone marrow and blood disorders which also have hyper-eosinophilia as a feature. Investigating a patient with hyper-eosinophilia is a priority, as it can speed up the potential diagnosis of CEL-NOS. This enables early initiation of treatment before any tissue damage becomes established, particularly heart fibrosis.

To determine if any damage to the patient’s organs has occurred, the following tests may be carried out:

• Blood chemistry tests to check that the liver, kidneys and spleen are working properly.
• Other tests to look out for changes in cardiovascular and pulmonary (heart and lung) systems. These include:
  • Chest X-rays
  • Echocardiography (ultrasound to create an image of the heart)
  • Pulmonary function test (a series of tests to determine the severity of pulmonary impairment)
  • Cardiac troponin T test (troponin T is a protein found in the cardiac muscles, which is released into the bloodstream when the heart is damaged)

2016 World Health Organisation diagnosis of CEL-NOS

Because patients with CEL-NOS and iHES both have hyper-eosinophilia and associated organ damage, the 2016 World Health Organisation (WHO) stipulates the following characteristics should be present for a diagnosis of CEL-NOS:

• Eosinophil count is greater than 1500 x 106/l in the peripheral blood
• The patient does not meet any of the WHO criteria for the following illnesses:
  • Chronic myeloid leukaemia (CML) with presence of BCR-ABL1 gene
  • Atypical BCR-ABL1-negative CML
  • Polycythaemia vera (excess of red blood cells)
  • Essential thrombocythaemia (excess of platelets with abnormal blood clotting)
  • Chronic neutrophilic leukaemia (excess of neutrophil white blood cells)
  • Chronic myelomonocytic leukaemia (excess of monocyte white blood cells)
  • Primary myelofibrosis (build-up of scar tissue in the bone marrow)
• No mutations in any of the following genes: PDGFRα, PDGFRβ and FGFR1 (Fibroblast growth factor receptor 1) and no PCM1 JAK2, ETV6-JAK2 or BCRJAK2 fusion genes
• Myeloblast cells in the peripheral blood and the bone marrow make up less than 20% of white blood cells, and there are no diagnostic features of AML, including the chromosome mutations inv(16) (p13.1q22) and t(16;16)(p13;q22)
• There is a clonal component to chromosome or gene abnormality or myeloblast cells are more than 2% in the peripheral blood or more than 5% in the bone marrow blood

Because CEL is a rare disease, rates of acute transformation into acute leukaemia or into blast crisis are unknown. Case reports indicate that CEL usually progresses slowly and can remain the same for many years, but then transform rapidly into AML or blast crisis in some cases.

The foundation of treatment of CEL-NOS is interferon, hydroxycarbamide and tyrosine kinase inhibitors such as imatinib.

Because CEL-NOS is so rare, there is no standard treatment. The course of CEL-NOS is different depending on the patient’s circumstances. Additionally, in some patients, CEL-NOS can be stable for many years and then transform into AML. Your haematologist will create a treatment plan suitable for you.

Chemotherapy

Chemotherapy involves using drugs to prevent cancer cells from growing and dividing, leading to the cancer cells being destroyed over time. Targeted chemotherapy is a chemotherapy treatment that targets the specific genes or proteins of leukaemia cells.

Patients with FIP1L1-PDGFRα gene or PDGFRα gene mutations

The targeted chemotherapy, imatinib, is a tyrosine kinase inhibitor which prevents the kinase activity of the FIP1L1- PDGFRα gene and stops the production of the abnormal eosinophils. CEL-NOS patients who have the FIP1L1-PDGFRα gene respond very well to treatment with low-dose imatinib. In selected cases, where no response is seen, the dose of imatinib may be increased.

Case reports of patients with PDGFRα gene mutations, or variants of PDGFRα other than FIP1L1-PDGFRα, have shown that imatinib can produce durable remissions in these patients. Patients with a PDGFRα mutation who received imatinib for a median duration of 6.6 years had a response rate of 96%, and their ten-year overall rate of survival was 90%. All the patients who achieved remission continued to respond to imatinib, and none of the patients showed any disease progression.

Chemotherapy options for other patients

It is estimated that approximately 10% to 20% of patients with CEL-NOS have the FIP1L1-PDGFRα gene. The goal of therapy in these patients is to prevent organ damage caused by the eosinophilia.

Hydroxycarbamide

Although not a cure, hydroxycarbamide is an effective chemotherapy for controlling hyper-eosinophilia. It can also be used in combination with steroids to improve the response rate. Chemotherapy drugs such as vincristine, chlorambucil, cyclophosphamide, etoposide, cyclosporine, and 2-chlorodeoxyadenosine can be used as second-line drugs, if hydroxycarbamide chemotherapy is not effective.

High dose imatinib

If the therapies above have not produced any results, higher doses of imatinib for patients without the mutated PDGFRα and PDGFRβ genes may eventually produce a response, if only partial. For many patients, even if they do not have these mutations, imatinib can improve blood counts and symptoms for many years, if the drug is taken on a regular basis.

Immunotherapy

Interferon-alpha (IFN-α) is a drug of purified derivative fractions of white blood cells. This immunotherapy helps boost the body’s natural immune system to fight the leukaemia. The use of IFN-α in CEL-NOS is partly guided by its known efficacy in CML, polycythaemia vera and essential thrombocythaemia. IFN-α is often used in CEL-NOS patients who do not respond to other therapies including steroids (prednisone) and hydroxycarbamide. It has shown reductions in white cell counts and reversed organ injury in patients with CEL-NOS.

Stem cell transplant

Allogeneic stem cell transplants, where blood-forming stem cells are donated from a genetically similar donor, are used in patients with aggressive CEL-NOS. While a stem cell transplant may be a treatment option for some patients, most people with CEL-NOS are older, so they may not be able to benefit from a stem cell transplant.

Survival following a stem cell transplant ranges from eight months to five years. Although success has been described in several cases, the role of stem cell transplants as a treatment for CEL-NOS is not well recognised.

Supportive care

Supportive or palliative care is medical care that relieves symptoms without dealing with the cause of the condition. Examples of supportive care for CEL-NOS include:

Leukapheresis – Leukapheresis is a procedure in which the excess white blood cells are separated out from the blood to help reduce the large numbers of eosinophils and reduce the thickening of the blood. This is achieved using an electrophoresis machine. However, it does not represent an effective maintenance therapy.

Blood-thinners – Anticoagulants (which thin the blood) and anti-platelet agents (which prevent blood clotting) help patients avoid getting clots and embolisms caused by their eosinophilia.

Splenectomy – A splenectomy is an operation to remove the spleen, which makes lymphocyte white blood cells, and it may be recommended for some patients. As the spleen becomes enlarged with the high number of eosinophils, it can cause patients severe abdominal pain. Splenectomy is not a standard treatment, but it can be a part of a palliative care treatment plan. A surgical oncologist is a doctor specialising in cancer surgery and will usually perform this procedure.

Cardiac surgery – Cardiac surgery may prolong survival in patients with cardiac heart disease. Heart valve replacements or surgery on scarred heart muscle can help recover heart function.

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 CEL-NOS?
• What tests will I need to have?
• What will the tests show?
• How long will the results take?
• How rare is CEL-NOS?
• 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 CEL 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.