Eosinophilia

Overview

• Eosinophils differentiate under the control of IL-5, IL-3, GM-CSF; normal blood eosinophils <0.5 × 10⁹/L.
• Eosinophil markers: CD23, CD25, CD69.
• Location: primarily tissues; also spleen, lymph nodes, thymus, GI tract.
• Hypereosinophilia: persistent absolute eosinophil count (AEC) >1.5 × 10⁹/L.
• Severity grading: 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 circulating blasts should prompt immediate bone marrow biopsy.

Secondary (reactive) eosinophilia

End-organ damage in hypereosinophilia

• The goal of therapy is to reduce eosinophil numbers and minimize the cytotoxic effects of eosinophil granule contents on tissues, preventing end-organ damage.
• Cardiac (most feared): eosinophilic myocarditis progressing to endomyocardial fibrosis and restrictive cardiomyopathy (classic Loffler endocarditis) with mural thrombus. Screen with troponin and TTE; add corticosteroids when there is cardiac involvement, especially elevated troponin or abnormal TTE.
• Thromboembolic: arterial and venous thrombosis.
• Constitutional / other systems: fever, fatigue, myalgia, pruritus, angioedema; cough and pulmonary infiltrates; diarrhea and GI involvement; skin and neurologic manifestations.

Primary eosinophilia

• Lymphocyte variant hypereosinophilia (L-HES)
• Dx: no standard criteria; aberrant T-cell population by flow (commonly CD3-CD4+), often with a clonal TCR rearrangement (supportive, not always demonstrable). Increased IL-5, TARC, and IgE.
• Sx: skin manifestations, adenopathy, rheumatologic manifestations; less commonly GI, pulmonary, neurologic, and cardiovascular. Usually indolent; patients may develop T-cell lymphoma or Sezary syndrome.
• Work up: PET or lymph node biopsy to rule out lymphoma; EBV viral load.
• Tx: corticosteroids, anti-IL-5, hydroxyurea, interferon.

• Chronic Eosinophilic Leukemia, NOS (CEL-NOS)
• Dx: persistent eosinophilia >1.5 × 10⁹/L, NO disease-defining markers (BCR-ABL, PDGFR, etc.) BUT presence of a clonal marker (cytogenetic or molecular) OR ≥2% peripheral blood blasts or 5 to 19% marrow blasts (WHO 2016). WHO 2022 renames it CEL and requires clonality AND abnormal marrow morphology (blasts <20%). Poor prognosis, can transform to blast phase. M>F, peak incidence 4th decade.
• Sx: fever, fatigue, cough, pruritus, diarrhea, angioedema, myalgia, and end-organ damage. Poor prognostic features: massive splenomegaly, cytogenetic abnormalities, dysplasia in BM.
• Tx 1st line (cytoreduction): hydroxyurea (IFNalpha if HU-refractory); consider allogeneic HCT for aggressive or transforming disease. Corticosteroids only for acute eosinophil-mediated organ injury, not as disease-modifying maintenance. Check for Strongyloides stercoralis and treat empirically with ivermectin in the appropriate context while serology returns.
• Tx 2nd line (for return of symptoms, organ damage, or rising eosinophils): hydroxyurea, IFNα if refractory to HU, methotrexate, cyclosporine, vincristine, alemtuzumab (anti-CD52).

• Fusion-driven myeloid/lymphoid neoplasms
• Similar to CML in biology and presentation but less common. All carry tyrosine kinase rearrangements/fusions; not all show prominent eosinophilia. BM with dysplastic/immature eosinophils hints at clonal origin. Tryptase and B12 may be elevated in myeloid neoplasms.
• PDGFRA fusion with FIP1L1: excellent prognosis, male predominance. Common partner FIP1L1 on 4q12; cryptic interstitial deletion of 4q12 (contains CHIC2) juxtaposes and produces an in-frame FIP1L1-PDGFRA fusion. Cannot be seen on standard cytogenetics: use RT-PCR and FISH (CHIC2 probe, uniformly deleted). Presents with eosinophilia, splenomegaly, MPN phenotype, but AML/ALL presentation can occur. Tx: imatinib; add steroids with cardiac involvement, especially elevated troponin or abnormal TTE. Pre-imatinib prognosis poor (historical heterogeneous-HES median OS ~9 mo, not FIP1L1-PDGFRA-specific); now 5-year OS >80%. Low-dose imatinib 100 to 400 mg/day (some once-weekly dosing to maintain CMR). Rarely develops T674I mutation with poor prognosis.
• PDGFRB fusion with ETV6: excellent prognosis. PDGFRB at 5q31 to q33; common partner ETV6 (more than 30 others known). Presents like MPN, MDS/MPN, aCML, JMML, or blast phase; eosinophilia not always present. Dx by cytogenetics t(5;12), FISH, or RT-PCR. Tx: imatinib 100 to 400 mg daily.
• FGFR1 fusions: aggressive, high rate of transformation to AML or T-ALL; presentation depends on fusion partner. Tx: intensive chemotherapy followed by transplant if possible. Midostaurin and ponatinib have limited efficacy; pemigatinib (oral FGFR1/2/3 inhibitor) FDA approved Aug 2022 for relapsed/refractory FGFR1-rearranged MLN (FIGHT-203), often as a bridge to transplant.
• JAK2 fusions: rare; PCM1-JAK2 most common (provisional in WHO 2016; full entity in WHO 2022 and ICC). Course resembles other TK-fusion disease despite JAK2. Presents like MPN or MDS/MPN but with aggressive/rapid progression to myeloid or lymphoid blast phase (IKZF1/EBF1/CDKN2A/B deletions are lymphoid-associated lesions, not a general AML-transformation mechanism). Induction → transplant; JAK2 inhibitors can be used but transplant is ultimately required.
• FLT3 fusions: rare; ETV6-FLT3 most common, high likelihood of transforming to T-ALL. FLT3 TKIs (sunitinib, sorafenib) give limited response; consider transplant early.
• ETV6-ABL1 fusion: t(9;12). Karyotype often inconclusive and FISH can miss small changes; combine ETV6/ABL1 FISH, RT-PCR, or RNAseq. Some present with MPN/CML-like phenotype; AML/ALL progression possible, worse with blast phase. TKIs (imatinib, nilotinib) effective in chronic phase; HSCT used infrequently with varied success, consider in young or refractory patients.

• Idiopathic hypereosinophilic syndrome (HES)
• Dx: do BM biopsy and FISH (to exclude a clonal myeloid neoplasm and detect PDGFRA) on all patients. Idiopathic HES requires: (1) persistent eosinophilia ≥1.5 × 10⁹/L on 2 occasions at least 2 weeks apart (ICOG-EO 2023; WHO 2022 requires 4 weeks; the older 6-month requirement was dropped); (2) no reactive cause; (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 present. If criteria 1 to 6 are met but there is no end-organ damage, it is best classified as idiopathic hypereosinophilia (rather than HES).
• Tx: prednisone (check for Strongyloides first). Taper slowly to the lowest effective dose; if in remission, maintain on prednisone 10 mg or lower indefinitely. Steroid-sparing anti-IL-5: mepolizumab (approved); benralizumab (anti-IL-5Rα) FDA approved for HES May 2026 for patients ≥12 years (NATRON); reslizumab (anti-IL-5) is approved for eosinophilic asthma, not HES; only limited early HES data (SCH55700, Klion 2004: transient responses with rebound).

2024 to 2026 updates

• Mepolizumab (Nucala) for HES: FDA Sept 25, 2020 for adults and pediatric patients ≥12 yo with HES ≥6 months without an identifiable non-hematologic cause; reduces eosinophils and symptom flares.
• Benralizumab (Fasenra) for HES: FDA May 13, 2026 for patients ≥12 yo with HES without an identifiable non-hematologic secondary cause (NATRON: ↓ risk of first flare ~65%, HR 0.35); 30 mg SC q4 wk.
• Benralizumab (Fasenra) for EGPA: FDA approved Sept 2024 for adults with eosinophilic granulomatosis with polyangiitis (MANDARA trial); an alternative to mepolizumab (approved for EGPA since Dec 2017).
• Dexpramipexole: oral eosinophil-depleting agent in development for HES, eosinophilic asthma, and EGPA; investigational.