Author:

Keywords:

Algorithms, Antineoplastic Agents, Cytogenetics, Humans, Hypereosinophilic Syndrome, Piperazines, Prognosis, Protein-Tyrosine Kinase, Pyrimidines, Receptor, Platelet-Derived Growth Factor alpha, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., T-Lymphocytes, mRNA Cleavage and Polyadenylation Factors, Science & Technology, Life Sciences & Biomedicine, Hematology, CELL MYELOPROLIFERATIVE DISORDER, BONE-MARROW-TRANSPLANTATION, CHRONIC MYELOID-LEUKEMIA, CHRONIC MYELOMONOCYTIC LEUKEMIA, PDGF RECEPTOR-BETA, GROWTH-FACTOR PDGF, INTERFERON-ALPHA, PULMONARY INVOLVEMENT, CYTOGENETIC REMISSION, IMATINIB MESYLATE, Benzamides, Imatinib Mesylate, Oncogene Proteins, Fusion, Protein-Tyrosine Kinases, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.