Chronic Eosinophilic Leukemia Hypereosinophilic Syndrome

Myeloproliferative hypereosinophilic diseases are defined by a persistent (>6 months) unexplained eosinophilia greater than 1.5 X 109/L, a hypercellular bone marrow with eosinophilia, and tissue damage. They are discriminated from idiopathic hypere-osinophilic syndrome by the presence of tissue damage, although this may indeed be artificial as tissue damage may be subclinical or occur in the future. While investigating these patients, a reactive cause of eosinophilia such as allergies, parasitic infections, and other malignancies (e.g., on detection of phenotypi-cally abnormal T lymphocytes56) should be assiduously excluded. Eosinophil morphology varies from normal to include abnormalities such as degranulation, cytoplasmic vacuolation, hypolobulation, or hyperlob-ulation. The presence of Chronic eosinophilic leukemia (CEL) is suggested by increased proportion of blasts, hepatosplenomegaly, raised serum tryptase, vitamin B12, and a cytogenetic abnormality. In some patients the diagnosis will only be apparent after transformation to acute myeloid leukemia.

The detection of cytogenetic abnormalities is useful in discriminating CEL from a reactive eosinophilia. Abnormalities involving 5q33 or 8p11 are most frequent and clonality has been demonstrated even in patients with normal cytogenetics by X-chromosome inactivation patterns.57 Abnormalities of 5q33, especially t(5;12)(q33;p13), produce the fusion oncogene TEL-PDGFRp with constitutive activation of the kinase domain of PDGFRp originally cloned by Golub.58 Variable morphological features have been described from chronic myelomonocytic leukemia (CMML)-like to atypical CML, as reviewed by Bain.59 Two other translocations involving the PDGFRfi gene are t(5;7)(q33;q11.2) and t(5;10) (q33;21.2). Rarer translocations associated with 8p11 involve the fibroblast growth factor receptor-1 (FGFR1) most commonly fusing with the ZNF198 gene of 13q12 generating t(8;13)(q11;q12); they are frequently associated with non-Hodgkin's lymphomas and have a particular tendency to leukemic transformation.60-63

Recently, a novel tyrosine kinase, FIP1L1-PDGFRa, has been described in 9/16 patients with hypere-osinophilic syndrome64 and 3/5 with systemic mastocy-tosis.65 This is generated by microdeletion of CHIC2 and is only detectable by RTPCR or FISH; conventional cytogenetics is unhelpful. Patients with FIP1L1-PDGFRa and eosinophilia have been reported to show a dramatic response to imatinib mesylate64,66 as have several with activated PDGFRB fusion tyrosine kinases.6768

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