Hypereosinophilic Syndrome (HES)

Eosinophil basics

• Eosinophils differentiate under the control of IL-5, IL-3, and GM-CSF. Normal blood eosinophils <0.5 ×10⁹/L. They primarily live in tissues (spleen, lymph nodes, thymus, GI tract).
• Markers: eosinophils express CD23, CD25, CD69.
• Hypereosinophilia: persistent absolute eosinophil count (AEC) ≥1.5 ×10⁹/L.
  • Mild: upper limit of normal to 1.5 ×10⁹/L.
  • Moderate: AEC 1.5 to 5 ×10⁹/L.
  • Severe: AEC >5 ×10⁹/L.
• AEC does NOT correlate with disease severity. Eosinophilia with cytopenia or blasts should prompt immediate bone marrow biopsy.

Hypereosinophilic syndrome: definition

• Diagnosis (HES): eosinophilia ≥1500 eosinophils (persistent, documented on at least two examinations about one month apart; the historical 6-month requirement is no longer used, treat urgently if organ damage), PLUS evidence of end-organ involvement attributable to hypereosinophilia, PLUS, for idiopathic HES, ruling out reactive/secondary causes (parasites, allergies, drugs); HES can also be reactive or neoplastic/clonal if organ injury is attributable to the eosinophilia
• Organ systems most commonly affected: skin, lungs, gastrointestinal tract, heart, and nervous system. Both neurologic involvement and endomyocardial fibrosis can be fatal.

Secondary (reactive) causes of eosinophilia

Lymphocytic variant hypereosinophilia (L-HES)

• Diagnosis: no standard criteria; an aberrant T-cell population by flow cytometry (often CD3-CD4+, IL-5 producing); a clonal TCR rearrangement is supportive but not always detectable; increased IL-5, TARC, and IgE (aberrant clone is often CD3-CD4+ producing IL-5).
• Symptoms: skin manifestations, adenopathy, rheumatologic manifestations; less commonly GI, pulmonary, neurologic, and cardiovascular. Usually indolent, but patients may develop T-cell lymphoma or Sezary syndrome.
• Workup: PET or lymph-node biopsy to rule out lymphoma; EBV viral load. Treatment: corticosteroids, anti-IL-5, hydroxyurea, interferon.

Chronic eosinophilic leukemia, NOS (CEL-NOS)

• Diagnosis: persistent eosinophilia ≥1.5 ×10⁹/L, NO disease-defining rearrangement (no BCR::ABL1, PDGFR, etc.), BUT presence of a clonal marker (cytogenetic or molecular) OR >2% peripheral-blood blasts or >5% marrow blasts (WHO 2016; WHO 2022 renames it CEL and requires clonality plus abnormal marrow morphology, blasts <20%). Poor prognosis; can transform to blast phase. M>F, median age at diagnosis about 55 to 62 years.
• Symptoms: fever, fatigue, cough, pruritus, diarrhea, angioedema, myalgia, end-organ damage. Poor prognostic features: massive splenomegaly, cytogenetic abnormalities, dysplasia in BM.
• Treatment, 1st line (cytoreduction): hydroxyurea (IFN-alpha if HU-refractory); evaluate for allogeneic HCT in aggressive or transforming disease. Corticosteroids are used acutely for eosinophil-mediated organ injury only (not disease-modifying); indefinite prednisone is not standard CEL maintenance. Check for Strongyloides stercoralis and treat empirically with ivermectin in the appropriate context while serology returns.
• Treatment, 2nd line (failure of HU and IFN-α): clinical trial or allogeneic HCT; vincristine, alemtuzumab (anti-CD52). Steroid-sparing options used mainly in idiopathic or lymphocytic-variant HES: methotrexate, cyclosporine, anti-IL-5: mepolizumab (approved); benralizumab (anti-IL-5Rα, FDA approved for HES May 2026, NATRON); reslizumab (approved for eosinophilic asthma, not HES; early HES study [SCH55700] showed eosinophil suppression with variable clinical response).

Fusion-driven myeloid/lymphoid neoplasms with eosinophilia

• Similar to CML in biology and presentation but less common; all carry a tyrosine-kinase rearrangement/fusion. Not all have prominent eosinophilia. Dysplastic/immature eosinophils in the marrow hint at clonal origin; tryptase and B12 may be elevated in myeloid neoplasms.

Idiopathic HES / idiopathic hypereosinophilia

• Do a bone marrow biopsy with cytogenetic/molecular studies and FISH (PDGFRA) to evaluate for and exclude a clonal myeloid neoplasm and FISH (to detect PDGFRA and related rearrangements) on all patients.
• Idiopathic HES criteria: (1) persistent eosinophilia (AEC ≥1.5 ×10⁹/L) documented on at least two examinations (about one month apart; no 6-month waiting period, treat urgently if organ damage) (in evolution, since treatment can be urgent); (2) no reactive cause of eosinophilia; (3) no associated clonal myeloid neoplasm (AML, MDS, MDS/MPN overlap, MPN, systemic mastocytosis); (4) no cytokine-producing, immunophenotypically aberrant T-cell population; (5) no increased myeloblasts in blood or marrow; and (6) no evidence of eosinophil clonality, WITH end-organ damage.
• If all six criteria are met EXCEPT there is no end-organ damage, it is best classified as idiopathic hypereosinophilia (rather than HES).

Treatment overview

• Steroids: frontline therapy for HES.
• Other agents: vincristine, hydroxyurea, interferon-α.
• Imatinib for FIP1L1/PDGFRA-positive disease or a 5q31 to q33 breakpoint (PDGFRB rearrangement, robust response). Imatinib can also be given to HES with myeloproliferative features lacking FIP1L1-PDGFRA who fail glucocorticoids or as a steroid-sparing agent; if no response to 100 mg daily, increase to 400 mg daily.
• Mepolizumab (anti-IL-5), FDA approved September 2020 for HES.
• Benralizumab (anti-IL-5Rα), FDA approved May 2026 for HES (NATRON).
• If pharmacologic management fails, consider allogeneic HCT.
• Key mutations recap: FIP1L1/PDGFRA (most common in HES, imatinib-responsive, also seen in mastocytosis); 5q31 to q33 / PDGFRB rearrangement (robust imatinib response); ETV6-PDGFRB [t(5;12)(q31 to q33;p13.2)] is the most common PDGFRB abnormality, with a hematologic presentation similar to CMML.