Hypereosinophilic Syndrome and Molecularly Targeted Therapy

Hypereosinophilic syndrome (HES) comprises a generally heterogeneous group of rare hematologic disorders defined by persistent eosinophilia and, frequently, associated end-organ damage. Recent advances in cellular and molecular biology have led to the pathogenetic categorization of HES into three subtypes or variants—myeloproliferative, lymphocytic, and idiopathic—which, in turn, has suggested a number of therapeutic strategies based on the disease variant. Recently, a subset of HES patients was found to harbor FIP1L1-PDGFRA, an aberrant fusion gene that encodes a constitutively activated tyrosine kinase. Imatinib mesylate is a well-known inhibitor of BCR-ABL, KIT, platelet-derived growth factor receptor alpha (PDGFRα), PDGFRβ, and other kinases and is currently used to treat chronic myelogenous leukemia, gastrointestinal stromal tumor, and several other malignant diseases caused by activated kinases. Emerging clinical evidence has shown that most patients with the FIP1L1-PDGFRA gene are responsive to imatinib. Further, a number of patients with FIP1L1-PDGFRA–negative disease or without an identified imatinib-sensitive target driving the disease have responded to imatinib therapy. Based on this clinical experience, a trial of imatinib therapy is clearly warranted in HES patients known to carry the FIP1L1-PDGFRA gene and also appears justified in patients who are FIP1L1-PDGFRA–negative or whose genotype is unknown.