Diagnostic And Treatment Paradigms

The diagnosis of HES or CEL requires exclusion of reactive causes of eosinophilia. According to WHO criteria,76 reactive causes include infections, hypersensitivity and allergic diseases, immune system disorders, metabolic abnormalities, and diseases of the connective tissue, heart, lungs, skin, and gastrointestinal systems. CEL remains, to a degree, a poorly defined entity.77 The most characteristic feature distinguishing CEL from HES is the presence of karyotypic abnormalities in the myeloid cells or presence of increased blast cells in the bone mar row (5-19%) or blood (more than 2%).76 Differential diagnoses further include malignant disorders in which eosinophilia is either reactive (e.g., secondary to tumor-producing hematopoietic growth factors) or where eosinophils are part of the hematopoietic malignant clone [e.g., CML, AML with inv(16) or t(8;21), MDS with t(1;7), hematologic malignancies involving rearrangement of transcription factor ETV6, MPD with t(5;12)(q33;p13), hematologic malignancies associated with rearrangement of 5q chromosome in the area coding for genes regulating eosinophilic growth factors, and other rare hematologic malignancies].

For the remaining cases which fulfill the original criteria for HES,78 the WHO criteria,76 and other criteria,77 79 further screening should include complete bone marrow examination, including histologic examination, karyotype analysis, FIP1L1-PDGFRa by PCR or FISH, and documentation of disease and eosinophil clonality by FISH or molecular methods. Abnormal T-lymphocyte subsets may be identified immunophenotypically as immature T cells (CD3+, CD4 , and CD8) or aberrant T cells (CD3" and CD4+),80'81 with or without rearrangement of T-cell receptor genes.80-83 The usefulness of determining interleukin 5 (IL-5) and other cytokines plasma concentrations is unknown. Association of eosinophilia with systemic mastocytosis84,85 supports the determination of plasma tryptase concentrations. Assessment of splenomegaly, hepatomegaly, abnormal marrow function (e.g., anemia, thrombocytopenia, marrow fibrosis, and dysplasia), and elevated plasma concentrations of tryptase helps define "myeloproliferative variant" and thus influences therapeutic decisions.86 The final pretreatment assessment should focus on identifying and grading the involvement of cardiovascular, pulmonary, neurologic, dermatologic, and other systems known to be involved in patients with hypere-osinophilia, and should help guide the risk-to-benefit ratio of a particular therapeutic approach. This consideration is particularly important with the use of novel, investigational treatments that were pioneered using imatinib mesylate.

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