Possible diagnostic and treatment algorithm for hypereosinophilia. (A) Patients whose workup is negative for secondary causes of eosinophilia subsequently undergo testing for the FIP1L1-PDGFRA gene fusion. Patients positive for the fusion are classified as having one category of FIP1L1-PDGFRA–positive (F-P⁺) clonal eosinophilia (eg, F-P⁺ chronic eosinophilic leukemia [CEL] or F-P⁺ systemic mastocytosis [SM] with eosinophilia). A negative test for the fusion would classify patients into 1 of 3 diagnostic groups based on additional laboratory criteria: CEL, unclassified; hypereosinophilic syndrome (HES); or T-cell–associated HES. (B) A trial of imatinib is recommended for FIP1L1-PDGFRA–positive CEL or SM patients. Conventional therapy or a trial of imatinib could be attempted for symptomatic FIP1L1-PDGFRA–negative patients. FIP1L1-PDGFRA–negative patients who demonstrate hematologic remissions with imatinib could be placed in a provisional category of imatinib-responsive (IR), warranting investigation of potential alternative targets of imatinib in these cases.