At a Glance

Chronic Eosinophilic Leukemia (CEL) is a chronic myeloproliferative neoplasm (CMPN) characterized by a clonal proliferation of eosinophilic precursors that leads to increased eosinophilia in the peripheral blood, the bone marrow and possibly peripheral tissues. Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues. In particular, chronic eosinophilic degranulation in cardiac tissues can lead to a restrictive cardiomyopathy due to endomyocardial fibrosis.

The diagnosis of CEL relies on evidence of eosinophilic clonality or increased blasts in the blood or bone marrow in patients with eosinophil counts greater than or equal to 1500 per microliter. Furthermore, cases of CEL must lack other feature of other CMPN or myelodysplastic (MDS) or myelodysplastic/myeloproliferative syndromes. Therefore, CEL must lack rearrangements of BCRABL, PDGFRα, PDGFRβ, FGFR1, or inv(16)(p13.1q22). Also, there must be no histomorphologic features of polycythemia vera, essential thrombocythemia, primary myelofibrosis, atypical chronic myeloid leukemia, or chronic myelomonocytic leukemia.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

CEL must be distinguished from reactive causes of eosinophilia. A thorough travel history to assess for parasitic, fungal, or mycobacterial infections must be performed. Many autoimmune diseases and connective tissue diseases can have an associated eosinophilia. Idiopathic/allergic reactions, including to medications, as well as environmental antigens, must be considered. Immune deficiencies, such as hyper-IgE syndrome, hyper-IgM syndrome, and IgA deficiency, can lead to eosinophilia.

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Reactive eosinophilias are also common in hematologic (e.g., acute lymphoblastic leukemia (ALL), Hodgkin lymphomas, T cell lymphomas, mastocytosis) and nonhematologic (e.g., lung, renal, breast, vascular, and female genital tract) malignancies. These reactive causes are nonclonal and are not CEL.

Once these reactive causes are excluded, a bone marrow biopsy to look for histomorphologic features of other myeloproliferative or myelodysplastic diseases is warranted. Karyotype, fluorescent in situ hybridization (FISH) for PDGFRα, and T-cell clonality by PCR are warranted. The rearrangements of PDGFRβ and FGFR1 can typically be detected by traditional G-banding karyotype. Conversely, the translocation of PDGFRα is often cryptic and requires FISH or polymerase-based chain reaction (PCR) techniques for detection. Because many T-cell lymphoproliferative disorders may be subtle and can be associated with reactive eosinophilia, assessment of T-cell clonality is recommended before the diagnosis of CEL is made.

World Health Organization (WHO) 2008 Diagnostic Criteria for CEL

Criteria include:

eosinophilia greater than or equal to 1500 per microliter (typically sustained for >6 months)

no evidence of another MPN, MDS, or MDS/MPN by bone marrow histology

no evidence of a BCRABL fusion and no evidence of rearrangements of PDGFRα, PDGFRβ, FGFR1

blast count is less than 20% in the blood and bone marrow and no evidence of a t(16;16)(p13.1;q22) or inv(16)(p13.1;q22)

blasts increased in blood (>2%) or bone marrow (>5%) OR cytogenetic or molecular genetic evidence of clonality

What other diseases should be considered in the differential? How do I distinguish between them?

Multiple reactive and clonal causes for eosinophilia exist. Reactive causes include chronic infections (i.e., parasitic, fungal, mycobacterial, and bacterial), allergies, autoimmunity, connective tissue disorders, immune deficiencies, and response to tumors.

Clonal eosinophilias also arise in myeloid neoplasia associated with PDGFRα (4q12), PDGFRβ (5q31-33), or FGFR1 (8p11) rearrangements. These are a separate category in the WHO 2008 classification.

The eosinophilias associated with PDGFR rearrangements show some sensitivity to imatinib and other tyrosine kinase inhibitors. PDGFRα rearrangements can also be seen in patients presenting with acute myeloid leukemia (AML) and precursor T-cell lymphoblastic lymphoma. FGFR1 rearrangements may also be associated with some lymphoid neoplasia, either precursor T-cell lymphoblastic lymphoma/leukemia or precursor B lymphoblastic lymphoma/leukemia. In these cases, the patients who present with these translocations in their acute leukemias often have a history of eosinophilia with no known cause and the acute leukemia likely represents a transformation of the undiagnosed CEL.

Core-binding factor AML with inv(16) or t(16;16) can also present with eosinophilia, may present with less than 20% blasts, and still meet criteria for AML if the chromosomal 16 abnormality is present. These translocations are detected by karyotype, and the cytology of AML with inv(16) is typically distinct from CEL, as it often shows a prominence of immature eosinophils with large basophilic granules.

Hypereosinophilic syndrome (HES) can be challenging to distinguish from CEL, as the only difference between the 2 is that HES does not have an increase in blasts and does not show evidence of clonality by karyotype or molecular genetic assays. Clinically, both CEL and HES have tissue involvement with associated fibrosis of lung, cardiac, or gastrointestinal tissues. Both may present with splenomegaly, neuropathy, or rheumatologic involvement. Both typically present in males between 20 and 50 years of age. Both typically show an expansion of the mature eosinophilic compartment in the blood with relatively few immature eosinophilic precursors.

The distinction is based on blast percentages (>2% in blood or >5% in marrow confirming CEL) or the proof of a clonal disorder with cytogenetics (e.g., +8, i(17q)) or molecular genetics. Those cases that meet the criteria for HES but lack tissue damage are best diagnosed as idiopathic hypereosinophilia. The syndromic designation of HES requires evidence of tissue damage.

What Lab Results Are Absolutely Confirmatory?

No single lab test is absolutely confirmatory. Bone marrow biopsy, karyotype, FISH for PDGFRα (4q12) rearrangements, and T-cell clonality analysis are all used to make the diagnosis.

What is the long-term prognosis in CEL patients?

Morbidity and mortality in CEL patients is primarily due to either tissue damage, particularly cardiac fibrosis, or transformation to AML in those patients who present with increased blasts. Previous studies have shown a heterogeneous range of survival due to the amalgamation of CEL patients with those with HES, idiopathic hypereosinophilia, and those with neoplasia associated with rearrangements of PDGFRα, PDGFRβ, and FGFR1. In one series, survival was approximately 80% at five years with negative prognostic factors being concomitant myeloproliferative neoplasia, increased blasts, increased eosinophils, cardiac involvement, and lack of responsiveness to corticosteroids.