Molecular alterations underlying eosinophilic and mast cell malignancies
Eosinophilic and mast cell disorders are uncommon hematologic entities, but they can carry significant morbidity and lead to devastating end-organ sequelae. In the past ten years, extensive work has led to the discovery of certain molecular abnormalities underlying a subset of these diseases. A significant minority of patients with clonal eosinophilia carry abnormal gene fusions involving PDGFRA, PDGFRB, and FGFR1. These findings have been quite significant, as those individuals with a FIP1L1-PDGFRA fusion have an exquisite susceptibility to tyrosine kinase inhibitors (TKIs), such as imatinib mesylate. Imatinib leads to a rapid remission in these patients and aborts the clinical trajectory of the disease. Unfortunately, TKIs have not been shown to be particularly active in the case of mastocytosis, although the majority of patients with mastocytosis carry a c-KIT alteration, a target of agents such as imatinib. The reason for this decreased sensitivity to TKIs is related to the resistance of the D816V variant of c-KIT, found in the majority of patients with mastocytosis. Nevertheless, investigation is ongoing to define new molecular lesions in these diseases, and potentially new targets for therapy. Clinical trials are also investigating other novel small molecules that may have efficacy against targets currently resistant to imatinib and other TKIs.