Abstract
PURPOSE OF REVIEW: This review examines the rapidly evolving landscape of myeloproliferative hypereosinophilic syndromes (HES) and related neoplasms. We aim to synthesize current understanding of their diverse molecular drivers, evaluate the efficacy of established and novel targeted therapies, and identify critical research gaps. The goal is to provide a clinically relevant update on how molecular precision is reshaping the diagnosis and management of these rare, often aggressive hematologic malignancies beyond the established standard of imatinib. RECENT FINDINGS: The field has moved beyond generic HES diagnoses to a molecularly defined classification. While imatinib remains the standard for PDGFRA/B-rearranged disease, resistance has spurred the development of next-generation inhibitors like avapritinib, which effectively targets the highly resistant PDGFRA D842V mutation. A major recent advance is the approval of pemigatinib for FGFR1-rearranged neoplasms, a historically chemo-refractory subgroup with a dismal prognosis. Clinical trials are also defining the roles of JAK inhibitors for JAK2-driven disease and exploring monoclonal antibodies like mepolizumab and benralizumab for symptom control in broader eosinophilic populations. SUMMARY: The management of myeloproliferative HES has transitioned from empirical therapy to a precision medicine paradigm. Early comprehensive molecular profiling is essential to guide therapy selection. While imatinib remains a cornerstone for select patients, novel agents like pemigatinib and avapritinib have filled critical therapeutic gaps. Future progress depends on the routine integration of comprehensive next-generation sequencing, the validation of minimal residual disease monitoring to guide therapy de-escalation, and international collaboration to conduct innovative trials for these rare patient populations.