Chronic Eosinophilic Leukemia: Epidemiology, Diagnosis, Prognosis

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm characterized by excessive eosinophil production, which can infiltrate tissues and cause organ damage. Unlike reactive eosinophilia, CEL is driven by clonal genetic abnormalities leading to uncontrolled proliferation. Early recognition is crucial, as unchecked progression may result in severe complications, including cardiac and pulmonary dysfunction.

Understanding its molecular drivers, clinical manifestations, and diagnostic criteria is essential for accurate identification and management. Given its rarity, prognosis varies widely based on individual patient factors, making risk stratification an important aspect of care.

Epidemiological Data

CEL is an exceptionally rare hematologic malignancy, with an estimated incidence of fewer than 0.05 cases per 100,000 individuals annually. Its precise prevalence is difficult to determine due to diagnostic challenges and overlap with other eosinophilic disorders. Population-based studies indicate CEL accounts for a small fraction of myeloproliferative neoplasms.

Most cases occur in adults over 50, though younger patients with genetic predispositions have been reported. There is no strong sex predilection, though some data suggest a slight male predominance. Ethnic and geographic variations remain poorly characterized due to the limited number of cases and the absence of comprehensive global registries. CEL is frequently misclassified as idiopathic hypereosinophilic syndrome (HES), complicating epidemiological assessments.

Advancements in molecular diagnostics have improved CEL classification. Retrospective analyses suggest some patients previously diagnosed with HES actually have CEL based on clonality and genetic mutations. This reclassification indicates CEL may be slightly more common than previously thought, though still exceedingly rare among myeloid neoplasms.

Molecular Characteristics

CEL is defined by clonal genetic abnormalities driving eosinophil proliferation. Unlike reactive eosinophilia, which results from secondary causes like infections or allergies, CEL arises from somatic mutations in hematopoietic progenitor cells, leading to autonomous expansion. These mutations disrupt pathways regulating cell growth and differentiation, contributing to disease progression.

Rearrangements of platelet-derived growth factor receptor genes (PDGFRA and PDGFRB) are among the most well-characterized genetic abnormalities. These mutations result in constitutive tyrosine kinase activation, driving unchecked proliferation. The FIP1L1-PDGFRA fusion gene, caused by an interstitial deletion on chromosome 4q12, is the most frequently identified molecular aberration. Patients with this mutation often respond well to tyrosine kinase inhibitors (TKIs) like imatinib. PDGFRB rearrangements, though less common, also lead to hypersensitive tyrosine kinase activity and show TKI responsiveness.

Other implicated mutations include JAK2, FLT3, and TET2. JAK2 V617F, commonly associated with myeloproliferative neoplasms, has been detected in some CEL cases, suggesting overlapping pathogenic mechanisms. TET2 mutations, affecting epigenetic regulation, may contribute to disease progression by altering hematopoietic stem cell function. These genetic alterations influence prognosis and treatment response, underscoring the importance of comprehensive molecular profiling.

Clinical Presentation

CEL symptoms arise from eosinophil accumulation in tissues. Early signs are often nonspecific, including fatigue, weight loss, and night sweats. As disease progresses, symptoms become more pronounced due to organ involvement.

Skin manifestations are common, with pruritus, urticaria, and eczematous eruptions frequently observed. More severe cases may present with angioedema or erythema, reflecting an intensified inflammatory response.

Gastrointestinal disturbances, including nausea, diarrhea, and abdominal pain, result from eosinophilic infiltration of the intestinal mucosa. Some patients develop eosinophilic gastroenteritis, characterized by mucosal thickening, malabsorption, and gastrointestinal bleeding, which can mimic other inflammatory or neoplastic disorders. Hepatic involvement may present as hepatomegaly or elevated liver enzymes, reflecting eosinophil-mediated tissue damage.

Neurological symptoms, though less common, can be debilitating. Peripheral neuropathy may cause paresthesia, muscle weakness, or autonomic dysfunction. Some patients experience cognitive disturbances, likely due to cerebral small-vessel involvement. These complications highlight the systemic nature of CEL and its potential for widespread tissue injury.

Diagnostic Workup

Diagnosing CEL requires distinguishing it from other eosinophilic disorders. A detailed clinical assessment, including history of eosinophilia and exclusion of secondary causes like infections or autoimmune diseases, is essential. A persistently elevated eosinophil count exceeding 1.5 × 10⁹/L raises suspicion but is insufficient for diagnosis.

Bone marrow aspiration and biopsy play a central role, often revealing increased eosinophilic precursors with atypical morphology. Flow cytometry and cytogenetic analysis help confirm clonality, differentiating CEL from reactive eosinophilia or idiopathic HES. Conventional karyotyping and fluorescence in situ hybridization (FISH) detect chromosomal rearrangements, while next-generation sequencing provides a comprehensive view of genetic mutations. Molecular testing for FIP1L1-PDGFRA, PDGFRB, and other relevant mutations is critical for confirming clonality and guiding treatment decisions.

Organ Involvement

Eosinophil infiltration in CEL leads to progressive organ dysfunction. The severity of involvement varies, depending on disease duration and eosinophil accumulation. Toxic granule proteins released by eosinophils contribute to inflammation, fibrosis, and structural damage.

Cardiac complications are among the most serious, often manifesting as endomyocardial fibrosis, restrictive cardiomyopathy, or thrombotic events. Persistent eosinophil infiltration into the myocardium can lead to myocardial necrosis, fibrosis, and ventricular dysfunction, sometimes resulting in Loeffler endocarditis. This condition increases the risk of heart failure, arrhythmias, and intracardiac thrombi.

Pulmonary involvement includes eosinophilic pneumonia, interstitial lung disease, and airway inflammation. Patients may present with dyspnea, cough, or wheezing, symptoms often mistaken for asthma. Imaging studies can reveal diffuse infiltrates, pleural effusions, or fibrosis.

Renal and neurological complications further contribute to disease burden. Eosinophil infiltration into the kidneys may cause glomerulonephritis, proteinuria, or acute kidney injury. Neurological involvement, though less frequent, can result in peripheral neuropathy, cerebrovascular events, or cognitive impairment due to vascular inflammation and thrombosis.

Prognostic Indicators

CEL prognosis varies based on molecular characteristics and organ involvement. Patients with FIP1L1-PDGFRA mutations generally respond well to TKIs like imatinib, often achieving long-term remission. In contrast, those without identifiable driver mutations or with high-risk genetic alterations (TET2, JAK2) tend to have more aggressive disease and reduced treatment responsiveness.

Clinical factors such as eosinophil count at diagnosis, bone marrow fibrosis, and organ dysfunction significantly impact prognosis. Markedly elevated eosinophil levels increase the risk of thrombotic complications and end-organ damage. Cardiac or pulmonary involvement is associated with worse outcomes, often leading to irreversible fibrosis and functional impairment.

Disease monitoring through molecular testing and imaging helps identify high-risk features early, guiding treatment decisions and improving patient outcomes.