Table 1. Subtypes of HES and appropriate therapy considerations.

Regardless of etiology, the presence of end-organ damage in HES requires prompt and aggressive initial workup and treatment, typically with glucocorticoids, to reduce eosinophil numbers and prevent further morbidity or mortality. Once work up is completed, steroid-sparing therapy can be further tailored according to HES subtype.

Category	Variant	Clinical and laboratory characteristics	Pathophysiology	First line therapies	Second line therapies
Primary	Chronic eosinophilic leukemia, not otherwise specified	Circulating myeloblasts and/or clonal cytogenetic abnormalities, cytopenias, constitutional symptoms, hepatomegaly, splenomegaly, may accelerate or transform into acute myeloid leukemia	Various mutations, including those involving KIT, JAK2 V617F, ETV6-PDGFRB, or ETV6-ABL1	Imatinib for ETV6-PDGFRB or ETV6-ABL1 mutations;	Chemotherapy; hematopoietic stem cell transplant
	Myeloid variant (M-HES)	Circulating leukocyte precursors and/or clonal cytogenetic abnormalities, cytopenias, hepatomegaly, splenomegaly, elevated serum B12 and tryptase levels (typically in FIP1L1-PDGFRA fusion only)	FIP1L1-PDGFRA fusion (most frequent genetic abnormality observed in M-HES)	Imatinib, often as little as 100 mg daily or less	Other tyrosine kinase inhibitors
			PDGFRA or PDGFRB rearrangement (nearly exclusive to males)	Imatinib	Other tyrosine kinase inhibitors; hydroxyurea
			FGFR1 rearrangement	Ponatinib; Midostaurin	Other tyrosine kinase inhibitors
			JAK2 point mutation or fusion	Ruxolitinib	Other kinase inhibitors
	Familial HES	HE is present at birth. Patients are often asymptomatic, but may rarely progress to end-organ damage	Unknown. Mutations have been mapped to 5q31-33 with autosomal dominant transmission.	Observation	GCs if necessary
Secondary	T cell lymphocytic variant (L-HES)	Typically with pronounced dermatologic findings and abnormal T cell immunophenotyping, may progress to T cell lymphoma	Clonal lymphoproliferative disorder, clones produce excess IL-5	GCs	IFN-α; JAK inhibitors; immunosuppressive agents; anti-eosinophil biologics
	Organ-restricted HES (EGID, EGPA, etc)	Symptoms of organ-specific disorders (e.g. gastrointestinal, sinopulmonary involvement)	Eosinophilic expansion in a single organ	Aimed at specific disorders (e.g. topical swallowed GCs for EGID); Cyclophosphamide	Methotrexate; Azathioprine; Rituximab; Mepolizumab (300 mg monthly dosing for EGPA)
	Parasitic infection	Exposure history may be suggestive. May have gastrointestinal symptoms, but may also be asymptomatic	Polyclonal eosinophilic expansion in response to parasites	Treat underlying infection
Idiopathic	n/a	Varied signs and symptoms, may affect any organ system	Unknown	GCs	Hydroxyurea; IFN-α; imatinib; anti-eosinophil biologics, immunosuppressive agents

Abbreviations: HES: hypereosinophilic syndromes; PDGFRB: platelet-derived growth factor receptor beta; FGFR1: fibroblast growth factor receptor 1; GC: glucocorticoid; IFN-α: interferon alpha; JAK2: Janus kinase 2; FIP1L1: Fip1-like1; PDGFRA: platelet-derived growth factor receptor alpha; L-HES: lymphocytic variant HES; IL-5: interleukin-5