Eosinophils are a type of white blood cell that form part of the body’s immune system. These have a protective immunity role against parasites and allergens.
A count of more than 1,500 eosinophils per µl of peripheral blood is associated with tissue damage and is called hyper-eosinophilia. Hyper-eosinophilic syndromes (HESs) are a group of rare illnesses characterised by a continued overproduction of eosinophils and is defined by a number of eosinophils of more than 1,500 cells per µl of blood for more than six months with associated organ damage attributable to the eosinophilia, but not explained by any obvious cause.
Chronic eosinophilic leukaemia (CEL) can be distinguished from HES by the presence of clonal molecular markers or significantly increased numbers of blasts cells. Clonal means that a group of identical eosinophil cells are multiplying in an unrestricted manner, and they are originating from immature cells in the bone marrow. Blasts is the name given to these immature bone marrow cells, which are often cancerous if present in large numbers.
What causes CEL?
Very rarely, CEL can be caused by a genetic mutation that develops during a person’s life due to environmental factors, smoking, and chemical/radiation exposure. However, for most patients, no specific cause can be found. There is no known cause for chronic eosinophilic leukaemia. It has not been linked to a specific chromosome or genetic abnormality.
Studies on the prevalence of CEL are rare and reliable data on CEL is not available given past difficulties of distinguishing CEL from HES.
The severity of CEL and its potential associated mortality in patients is mainly due to either tissue damage, particularly thickening and scarring of the heart, or transformation to acute myelogenous leukaemia (AML) in patients with high levels of blast cells.
Evidence from case reports indicates that CEL usually progresses slowly and may stay the same for many years. However, in some people, it may change quickly into acute AML.
Signs and symptoms of CEL
In around 10% of patients, CEL is diagnosed by chance in the early stages because the patient does not have any signs or symptoms. CEL may be found during a routine blood test.
Patients with CEL may experience the following symptoms or signs:
- Night sweats
- Unexplained weight loss
- Unexplained fatigue or shortness of breath
- Swollen lymph nodes (small swellings in the lymphatic system where lymph is filtered, and lymphocytes are formed. It is part of the immune system)
- Muscle pains (myalgias)
- Anaemia (low level of red blood cells and haemoglobin which is carried by the red blood cells)
- Thrombocytopenia (decrease in the levels of platelets, which are small blood cells that help the body form clots to stop bleeding)
- Mucosal ulceration
- Endomyocardial fibrosis (fibrosing of the inside of the heart lining)
- Splenomegaly (enlarged spleen)
CEL is more common in men, with peak incidence at around 40 years of age. However, diagnosis is rare as this disease type can be excluded and requires exceptional skill to be confirmed.
The diagnosis of CEL is based on the presence of clonal cancerous proliferation of eosinophilic cells and the exclusion of other bone marrow cancers and blood disorders where eosinophilia is a feature.
The WHO 2017 update of defined eosinophilic disorders gives the characteristics of an individual with CEL, NOS as:
- Eosinophil count is greater than 1500 per µl of peripheral blood
- The patient does not meet any of the WHO criteria for the following illnesses:
- Chronic myeloid (bone marrow) leukaemia (CML): presence of BCR-ABL1 is positive for CML
- Polycythaemia vera (proliferation of red blood cells)
- Essential thrombocythemia (excess production of platelets leading to abnormal blood clotting)
- Primary myelofibrosis (build-up of scar tissue in the bone marrow)
- Chronic neutrophilic leukaemia (excess production of white cells called neutrophils)
- Chronic myelomonocytic leukaemia (excess production of white cells called monocytes)
- Atypical chronic myeloid leukaemia (unusual type of CML)a
- Genetic testing does not show:
- Any rearrangement disorder of the following genes:
o PDGFRa (platelet-derived growth factor receptor alpha)
o PDGFRb (platelet-derived growth factor receptor beta)
o FGFR1 (fibroblast growth factor receptor 1 is a protein involved in growth and proliferation of cells in the body and is commonly activated in human cancers)
- The presence of any of the following fusion genes:
- Both of these following are met:
- The number of blast cells in the peripheral blood and the bone marrow is less than 20%
- The following are absent:
o Abnormalities in the inv(16)(p13.1q22) and t(16;16)(p13;q22) genes
- Other diagnostic features of AML
- Either of the following are met:
- There is a clonal component to the cell genetics or an abnormality present in the molecular genetics
- Blast cells are less than 2% in the peripheral blood or greater than 5% in the bone marrow.
HES patients that have been revealed to have a deletion in chromosome 4, which fuses the FIP1‑like-1 gene (FIP1L1) to the PDGFRA gene, leading to FIP1L1-PDGFRA rearrangement are now reclassified as having CEL because the FIP1L1-PDGFRA gene is considered a strong indicator of a clonal/cancerous disease. Possession of this clonal gene abnormality has been proposed as a new marker for CEL.
The diagnosis of CEL generally starts with a visit to your general practitioner, or if a routine blood test suggests there is abnormality with your blood.
Investigating a patient with HES is a priority, since the accurate detection of CEL can speed up the diagnosis and early initiation of treatment before involvement of heart fibrosis becomes established is paramount.
Initial diagnostic tests include:
- Complete blood cell counts to measure the number and quality of white blood cells, red blood cells and platelets.
- Blood chemistry tests to check that the liver, kidneys and spleen are normal in size and working properly.
If reactive/parasitic eosinophilia is unlikely, changes in cardiovascular and pulmonary (heart and lung) systems may be investigated. In the presence of cardiopulmonary disease, the following tests are needed:
- Chest X-ray
- Echocardiography (ultrasound to create an image of the heart)
- Pulmonary function test (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)
If the reactive causes for the eosinophilia are have been rejected or if a hematopoietic disease (disease of the bone marrow, spleen or lymph nodes) is suspected, analyses of the FIP1L1-PDGFRa, PDGFRb) and BCR/ABL gene rearrangements can be carried out.
To help confirm a diagnosis, the bone marrow may be examined for the following:
- Cell genetic abnormalities
- Karyotyping, which involves examination of the number and appearance of chromosomes to detect abnormalities.
The results of these tests will enable the oncologist to determine if the patient meets the WHO diagnostic criteria for CEL, NOS.
Risk of transformation
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.
Treatment of CEL
Given that chronic eosinophilic leukaemia is rare, current knowledge is that CEL develops differently in different people. It can be stable for many years and then quickly change into AML or other blood cancers. Similarly, it occurs mainly in middle age patients but can also present in young adolescents. As a result, there is no standard treatment plan for chronic eosinophilic leukaemia. Your physicians will create a treatment plan for you.
Chemotherapy and immunotherapy
Chemotherapy involves using drugs to prevent cancer cells from growing and dividing, which destroys the cancer cells overtime. Targeted therapy is a treatment that targets the specific genes or proteins of leukaemia cells, as in the case of imatinib. Imatinib prevents the tyrosine kinase enzymes from working and this can destroy the abnormal eosinophils by blocking the FIP1L1-PDGFRa gene. Therefore, it is more probable that imatinib will work for patients with this genetic mutation.
- CEL patients who are FIP1L1-PDGFRa positive respond very well to treatment with low doses of imatinib (100mg/day). In general, patients show good responses, achieving normal blood cell counts and most attain molecular remission (there is where there no demonstrable FIP1L1‑PDGFRa gene in the blood within 4 weeks of starting treatment). In selected cases, where no response is seen, or if some residual disease is present, the dose of imatinib may be increased to 400mg/day.
- For patients who do not have the FIP1L1‑PDGFRa gene which responds to imatinib, the treatments which are used in other blood marrow cancers may be helpful. It is estimated that only approximately 10%–20% have the FIP1L1‑PDGFRa gene.The goal of therapy is to prevent organ damage which is caused by the eosinophilia.
- Although not a cure, hydroxycarbamide is an effective chemotherapy to control the eosinophilia. A typical starting dose is 500 to 1000mg/day. It can also be used in combination with steroids to try and increase 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.
- If the therapies above have not yielded results, higher doses of imatinib for cases without the PDGFRαand PDGFRβgene rearrangements may eventually produce a response, if only partial. But, even if a patient does not have this mutation, it is still possible that imatinib may work. For many patients, imatinib can improve blood counts and symptoms for many years, if the drug is taken on a regular basis.
Interferon-a (IFN-a), is a purified derivative from fractions of white blood cells from the blood, and is called immunotherapy as it is actually a natural part of your body’s immune system. Immunotherapy helps to boost the body’s natural immune systemto fight the leukaemia.
IFN-a has shown reductions in white cell counts and reversed organ injury in patients with CEL. The use of IFN-a in CEL is partly based on its efficacy in CML. IFN-a is often used in CEL patients who do not respond to other therapies including steroids(prednisone) and hydroxycarbamide.
Stem cell transplant
Stem cell allogeneic transplantation (receipt of blood‑forming stem cells from a genetically similar, but not identical, donor) is used in patients with aggressive disease. A stem cell transplant may be a treatment option for some people with chronic eosinophilic leukaemia. Most people with chronic eosinophilic leukaemia are older so they may not benefit from a stem cell transplant, but it may be suited for the younger patient.
Disease-free survival following stem cell transplantation ranges from eight months to five years. Although success has been described in several cases, the role of transplantation is not well established.
Supportive care and surgery
Supportive or palliative care is medical care that relieves symptoms without dealing with the cause of the condition.
Leukapheresis is a procedure in which the excess white blood cells are separated out from a sample of blood to help reduce the large numbers of eosinophils/white cells. However, it does not represent an effective maintenance therapy. Anticoagulants (which thin the blood) and anti-platelet agents (which prevent blood clotting) help patients avoid getting clots and embolisms caused by their eosinophilia.
A splenectomy, which is an operation to remove the spleen, that is also known to make white blood cells in addition to the bone marrow, may be recommended for some patients. As the spleen becomes enlarged with the high number of eosinophils, it causes severe abdominal pain for the patient. This not standard treatment, but can be a part of a palliative care treatment plan. A surgical oncologist who is a physician specialising in cancer surgery will usually perform this procedure.
Palliative cardiac surgery may prolong survival in patients with end-stage heart disease. Heart valve replacements or surgery on the heart muscle which is scarred can help recover heart function.
When making treatment plan decisions, patients are often encouraged to consider clinical trials as an option they may give access to new treatments being investigated. Your physician can guide you in this decision.
Antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), have been developed, but are still in the early research stages research.