With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). In this study, we have stratified HES patients according to their FIP1L1-PDGFRA mutational status and criteria suggestive of a myeloid neoplasm. The peripheral blood and bone marrow specimens were evaluated for dysplastic eosinophils on peripheral smear (abnormal nuclear lobation, uneven granulation, hypogranulation, agranulation), serum B12 level 1000 pg/ml, serum tryptase level 12 ng/mL, anemia and/or thrombocytopenia, bone marrow cellularity >80% with left shift in maturation, dysplastic (spindle-shaped) mast cells on bone marrow biopsy, evidence of reticulin brosis 2+ on bone marrow biopsy, and dysplastic megakaryocytes on bone marrow biopsy. Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with 4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy. The primary outcome was an eosinophil count <1.5 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. In addition, a retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily 1 month) were classified according to the criteria used in the prospective study. Overall results showed that imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of 4 myeloid features was the sole predictor of response. After 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remained in remission off therapy for a median of 29 months (range 14-36). In conclusion, clinical features of MHES predict imatinib response in PDGFRA-negative HES.
