Chronic eosinophilic leukemia (CEL) is a rare, malignant blood cancer belonging to the group of myeloproliferative neoplasms. It is characterized by the uncontrolled production of eosinophils, a type of white blood cell, within the bone marrow. Eosinophils are normally part of the immune system, but their overproduction leads to high numbers circulating in the blood and infiltrating various organs. CEL is distinct from other forms of eosinophilia because it is clonal, meaning the abnormal cells originate from a single, mutated precursor cell. Understanding the specific genetic changes driving this malignancy is important, as these drivers dictate the disease’s progression and the most effective treatment strategies.
Understanding Chronic Eosinophilic Leukemia
CEL is classified as a myeloproliferative neoplasm, a category of disorders where the bone marrow produces too many of one or more types of blood cells. In CEL, the primary abnormality is the overgrowth of eosinophil precursors, resulting in a persistent and excessive number of mature eosinophils in the blood, defined as an absolute count greater than 1.5 x 10⁹/L. These cells usually protect the body against parasites and contribute to allergic responses, but in CEL, they accumulate and cause damage to tissues throughout the body.
It is important to distinguish CEL from hypereosinophilic syndrome (HES). HES is a diagnosis of exclusion for patients with unexplained, sustained eosinophilia and associated organ damage. The defining difference is that CEL is proven to be a clonal, malignant process, often by identifying a specific genetic abnormality. When a clear clonal marker is not found, the diagnosis defaults to CEL “not otherwise specified” (CEL-NOS) or idiopathic HES.
Identifying the Genetic Drivers
The most significant genetic driver of CEL involves a specific type of mutation that creates a fusion gene, leading to the uncontrolled growth of blood cells. This genetic change occurs during a person’s lifetime and is not inherited, meaning it is a somatic mutation. The most common and clinically relevant driver is the FIP1L1-PDGFRA fusion gene.
This fusion gene results from a small deletion of genetic material on chromosome 4, which joins a portion of the FIP1L1 gene with the PDGFRA gene. The resulting FIP1L1-PDGFRA fusion protein is a constitutively active tyrosine kinase, a type of enzyme that acts as an “always-on” growth signal. This constant signaling bypasses the normal regulatory mechanisms, causing the eosinophil precursors to proliferate without restraint.
While FIP1L1-PDGFRA is the predominant driver, other, less common gene rearrangements can also cause CEL. These include fusion genes involving PDGFRB and FGFR1. Similar to the PDGFRA rearrangement, these abnormalities result in the creation of an overactive tyrosine kinase protein. The presence of these specific fusion genes confirms the diagnosis of CEL and directly influences the choice of treatment.
Clinical Presentation and Diagnosis
The symptoms of CEL arise from the high number of eosinophils and the toxic substances they release as they infiltrate various organs. Common complaints include unexplained fever, night sweats, and unintentional weight loss, often accompanied by fatigue. The most concerning complications involve the heart, where eosinophil infiltration can lead to endomyocardial fibrosis, causing serious cardiac issues.
Other affected systems may include the skin, leading to rashes and swelling, and the nervous system, potentially causing peripheral neuropathy or confusion. Physical examination may reveal an enlarged spleen or liver (splenomegaly or hepatomegaly) due to the accumulation of abnormal cells.
The diagnostic process begins with a complete blood count, which shows the hallmark hypereosinophilia. However, this finding alone is insufficient for a CEL diagnosis, as many conditions, such as parasitic infections or allergies, can cause reactive eosinophilia. Therefore, secondary causes of eosinophilia must be carefully ruled out.
A definitive diagnosis requires evidence of clonality, typically obtained through a bone marrow biopsy and genetic testing. The bone marrow sample allows pathologists to check for an increase in eosinophil precursors and rule out other myeloproliferative disorders. Genetic testing, often using techniques like fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR), is performed to specifically search for the FIP1L1-PDGFRA fusion gene or other rearrangements like PDGFRB and FGFR1.
Targeted and Standard Treatment Strategies
Treatment for CEL is highly dependent on the genetic drivers identified during the diagnostic workup. The discovery of the FIP1L1-PDGFRA fusion gene has revolutionized the treatment for this specific subset of patients. For individuals with a PDGFRA rearrangement, the preferred first-line treatment is a targeted therapy using a drug called imatinib.
Imatinib is a tyrosine kinase inhibitor (TKI) that works by blocking the activity of the continuously active FIP1L1-PDGFRA fusion protein. The drug is effective, often leading to rapid clinical and hematologic responses, with complete molecular remission frequently observed within a few months. In patients with heart involvement, corticosteroids are often given alongside imatinib initially to reduce the risk of acute cardiac injury.
For patients who are negative for the PDGFRA, PDGFRB, or FGFR1 rearrangements, the disease is classified as CEL-NOS, and treatment is less straightforward. These patients do not have a specific target for TKIs like imatinib, so they receive conventional therapies aimed at reducing the eosinophil count. Standard treatment options include corticosteroids, which reduce inflammation and eosinophil production, or chemotherapy agents such as hydroxyurea or interferon-alpha.
In cases where the disease is high-risk or resistant to initial therapies, a more intensive treatment approach may be necessary. This can involve allogeneic hematopoietic stem cell transplantation (HSCT), where a patient’s diseased bone marrow is replaced with healthy stem cells from a donor. HSCT is reserved for advanced or refractory cases due to the complexity and risks associated with the procedure.