- Eosinophils are white blood cells that play roles in immunity and tissue homeostasis. Their differentiation and maturation is regulated by cytokines like IL-5. - Hypereosinophilic syndrome (HES) is defined by blood hypereosinophilia or tissue eosinophilia with evidence of end-organ damage and no alternative cause. - HES has a variety of presentations affecting the skin, lungs, heart, nervous system, and more. Prompt treatment is important to prevent serious complications. - HES subtypes include myeloproliferative, lymphocytic, and idiopathic forms based on features of myeloproliferation or clonal lymphocyte populations.

2. Learning Objectives
• Describe the mechanism of eosinophilia in hypereosinophilic
syndrome (HES) and how this can be targeted using biologic agents
• Perform differential diagnosis of eosinophilic disorders to identify
patients with HES
• Develop patient-specific treatment plans based on HES subtype
• Discuss the safety and efficacy of new and emerging biologic
treatments for HES

3. Mechanism and Pathophysiology
of Hypereosinophilia

4. Overview of Eosinophil Function
Eosinophils are a type of white blood cell with
multifunctional roles in humans:
Liao W, et al. Clinic Rev Allerg Immunol. 2015;50(2):125-139.
Protection from parasitic infections
Modulation of innate and adaptive immune responses
Release of immunoregulatory cytokines and signaling
molecules
Tissue homeostasis

5. Eosinophil Morphology
Rosenberg HF, et al. Nat Rev Immunol. 2012;13:9-22.
Human eosinophils contain:
• Multilobed nuclei
• Large red-stained cytoplasmic secretory
granules
Granules contain cytotoxic proteins:
• Major basic protein
• Eosinophilic cationic protein
• Eosinophilic peroxidase
• Eosinophil-derived neurotoxin
• Other cationic proteins, cytokines,
chemokines, growth factors, and
enzymes
Image courtesy of Spencer LA et al. Front Immunol. 2014;5:496. CC BY 4.0.
Secretory
Granules

6. Pathogenesis of Eosinophils
• Activated eosinophils cause pathogenicity by:
1. Direct cytotoxic effects through degranulation
2. Recruitment and/or activation of inflammatory cells through release of
proinflammatory mediators
• In pathogenic states, activated eosinophils can play a role in tissue
fibrosis, thrombosis, vasculitis, and allergic inflammation
Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.

7. Eosinophils Mature in the Bone Marrow
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. O'Sullivan JA, Bochner BS. J Allergy Clin Immunol. 2018;141(2):505-517.
Image courtesy of Johnston LK, Bryce PJ. Front Med. 2017;4:51. CC BY 4.0.
Common myeloid
progenitor (CMP)
Pre-granulocyte
macrophage progenitor
(GMP)
GMP Eosinophil precursor
(EoPre)
Eosinophil lineage–
committed progenitor (EoP) Mature eosinophil
• Eosinophils develop from progenitor cells that give rise to myeloid lineages
• GATA-1: transcription factor influencing erythroid development
• IL-5: major role in maturation and proliferation of eosinophils
• During development, toxic granule proteins must be sequestered to maintain cell viability

8. Eosinophils Mature in the Bone Marrow
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. O'Sullivan JA, Bochner BS. J Allergy Clin Immunol. 2018;141(2):505-517.
Image courtesy of Johnston LK, Bryce PJ. Front Med. 2017;4:51. CC BY 4.0.
Common myeloid
progenitor (CMP)
Pre-granulocyte
macrophage progenitor
(GMP)
GMP Eosinophil precursor
(EoPre)
Eosinophil lineage–
committed progenitor (EoP) Mature eosinophil
• Eosinophils develop from progenitor cells that give rise to myeloid lineages
• GATA-1: transcription factor influencing erythroid development
• IL-5: major role in maturation and proliferation of eosinophils
• During development, toxic granule proteins must be sequestered to maintain cell viability

9. Eosinophils Mature in the Bone Marrow
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. O'Sullivan JA, Bochner BS. J Allergy Clin Immunol. 2018;141(2):505-517.
Image courtesy of Johnston LK, Bryce PJ. Front Med. 2017;4:51. CC BY 4.0.
Common myeloid
progenitor (CMP)
Pre-granulocyte
macrophage progenitor
(GMP)
GMP Eosinophil precursor
(EoPre)
Eosinophil lineage–
committed progenitor (EoP) Mature eosinophil
• Eosinophils develop from progenitor cells that give rise to myeloid lineages
• GATA-1: transcription factor influencing erythroid development
• IL-5: major role in maturation and proliferation of eosinophils
• During development, toxic granule proteins must be sequestered to maintain cell viability

10. Eosinophils Mature in the Bone Marrow
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. O'Sullivan JA, Bochner BS. J Allergy Clin Immunol. 2018;141(2):505-517.
Image courtesy of Johnston LK, Bryce PJ. Front Med. 2017;4:51. CC BY 4.0.
Common myeloid
progenitor (CMP)
Pre-granulocyte
macrophage progenitor
(GMP)
GMP Eosinophil precursor
(EoPre)
Eosinophil lineage–
committed progenitor (EoP) Mature eosinophil
• Eosinophils develop from progenitor cells that give rise to myeloid lineages
• GATA-1: transcription factor influencing erythroid development
• IL-5: major role in maturation and proliferation of eosinophils
• During development, toxic granule proteins must be sequestered to maintain cell viability

11. Eosinophils Mature in the Bone Marrow
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. O'Sullivan JA, Bochner BS. J Allergy Clin Immunol. 2018;141(2):505-517.
Image courtesy of Johnston LK, Bryce PJ. Front Med. 2017;4:51. CC BY 4.0.
Common myeloid
progenitor (CMP)
Pre-granulocyte
macrophage progenitor
(GMP)
GMP Eosinophil precursor
(EoPre)
Eosinophil lineage–
committed progenitor (EoP) Mature eosinophil
• Eosinophils develop from progenitor cells that give rise to myeloid lineages
• GATA-1: transcription factor influencing erythroid development
• IL-5: major role in maturation and proliferation of eosinophils
• During development, toxic granule proteins must be sequestered to maintain cell viability

12. Regulation of Eosinophil Production, Trafficking,
and Apoptosis
• Dependent on interactions between transcription factors
(eg, GATA-1), cytokines (eg, IL-5), and other immune signaling
• Eosinophil differentiation and migration mediated by:
• Cytokines (IL-5)
• Chemokines (eotaxins)
• Nonchemokine factors (complement factors)
• Immune cells (lymphocytes, mast cells, and eosinophils themselves)
Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015(1):92-97.

13. After Maturation, Eosinophils Traffic Through
the Blood to Tissues
1. Johnston LK, Bryce PJ. Front Med. 2017;4:51.
2. Marichal T, et al. Front Med (Lausanne). 2017;4:101.
3. Kanda A, et al. Allergol Int. 2021;70(1):9-18.
Bone
Marrow
Image courtesy of Johnston LK, Bryce PJ.
Front Med. 2017;4:51. CC BY 4.0.
• Briefly found in the peripheral vasculature
(half-life, ~18 hours)
• Half-life in tissues tends to be longer
(1 to 7 days, depending on cytokine milieu)
• Eotaxins: CC chemokines influencing eosinophil
migration
IL-5
IL-5
IL-13
IL-4

14. Summary
• Eosinophils are white blood cells with multifunctional roles
• Eosinophil differentiation and maturation is mediated by:
• Cytokines (IL-5, IL-33)
• Nonchemokine factors (complement factors)
• Immune cells (lymphocytes, mast cells, and eosinophils themselves)
• After maturation, eosinophils migrate through the blood to tissues, a
process mediated by eotaxins and other signaling molecules

15. Hypereosinophilia and HES

16. Overview of HES
• Classification schema
• Diagnostic criteria
• Common presenting symptoms
• Secondary causes

17. Classification of Eosinophilia
1. Gotlib J. Am J Hematol. 2011;86(8):677-688.
2. Klion AD. Blood. 2015;126(9):1069-1077.
Eosinophilia severity
Absolute eosinophil
count (AEC)
Mild 500-1500/mm3
Moderate 1500-5000/mm3
Severe >5000/mm3
Blood Eosinophilia Classification1
At least 1 of the following criteria:
Eosinophils >20% of nucleated cells in bone
marrow
Markedly increased tissue infiltration,
according to experienced pathologist
Extensive extracellular deposition of
eosinophil-derived proteins on
immunostaining
Tissue Eosinophilia2

18. Definition of Hypereosinophilic Syndrome (HES)
Broadly, HESs are often considered to be defined as:
1. Blood hypereosinophilia (AEC ≥1500/mm3) or marked tissue eosinophilia
AND
2. Evidence of end-organ involvement with clinical manifestations
AND
3. No alternative diagnosis (no infection, no malignancy, no drug reaction)
Klion AD. Blood. 2015;126(9):1069-1077.
HESs have a spectrum of presentations, and there is no universally
agreed upon definition of HES

19. Common Presentations of HES, by Organ System
CNS, central nervous system; DVT, deep vein thrombosis; GI, gastrointestinal.
Ogbogu PU, et al. J Allergy Clin Immunol. 2009;124(6):1319-25.e3.
38%
26%
15%
8%
6%
6%
6%
4%
Skin
Lungs
GI tract
Musculoskeletal system
Constitutional symptom
Heart
CNS
Hematology
Initial Clinical Manifestations of HES in a Retrospective Cohort Study
Examples of Signs/Symptoms
Pruritis, dermatitis, urticaria, edema
Asthma, sinusitis, cough, dyspnea
Abdominal pain, vomiting, diarrhea
Myalgia, arthralgia
Malaise, weight loss, fatigue, fever
Congestive heart failure, myocarditis
Paresthesia, vertigo, visual disturbance
DVT, anemia
Proportion of Patients (n = 188)
With Organ System Affected

20. Appropriate Treatment of HES Is Critical
• ~20% of patients with HES eventually experience:
• Cardiovascular disease (eg, congestive heart failure, thromboembolic events)
• Can be irreversible
• Most common cause of morbidity and mortality
• Neurologic complications
• Most commonly cerebrovascular disease
1. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.
2. Ogbogu PU, et al. J Allergy Clin Immunol. 2009;124(6):1319-25.e3.
3. Abo Shdid R ,et al. Case Rep Oncol. 2021;14:249-255.
4. Lee D, Ahn TB. J Neurol Sci. 2014;347(1-2):281-287.
As HES progresses, the proportion of patients experiencing
serious complications increases.

21. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial

22. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL

23. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL
Clonal T Cells No T-Cell Clone
Populations of T cells
secreting eosinophil
hematopoiesis

24. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL
Clonal T Cells No T-Cell Clone
Organ-
restricted
eosinophilic
disorders
Populations of T cells
secreting eosinophil
hematopoiesis

25. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL
Organ-
restricted
eosinophilic
disorders
Eosinophilia in
association with a
defined diagnosis,
such as IBD or EGPA
Populations of T cells
secreting eosinophil
hematopoiesis
Clonal T Cells No T-Cell Clone

26. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL
Benign
Asymptomatic
with no evidence
of organ
involvement
Episodic
Cyclic
angioedema
and
eosinophilia
Other
Symptomatic
without features of
myeloproliferative or
lymphocytic forms
Organ-
restricted
eosinophilic
disorders
Eosinophilia in
association with a
defined diagnosis,
such as IBD or EGPA
Populations of T cells
secreting eosinophil
hematopoiesis
Clonal T Cells No T-Cell Clone

27. HES Classification
Simon HU, et al. J Allergy Clin Immunol. 2010;126(1):45-49.
HESs
Myeloproliferative
forms
Lymphocytic
forms
Overlap Undefined
Associated Familial
Myeloproliferative
HES
Features of
myeloproliferative
disease without proof
of clonality
CEL
Clonal eosinophilia,
including
FIP1L1/PDGFRA-
positive CEL
Benign
Asymptomatic
with no evidence
of organ
involvement
Episodic
Cyclic
angioedema
and
eosinophilia
Other
Symptomatic
without features of
myeloproliferative or
lymphocytic forms
Organ-
restricted
eosinophilic
disorders
Eosinophilia in
association with a
defined diagnosis,
such as IBD or EGPA
Family history of
documented persistent
eosinophilia of
unknown cause
Populations of T cells
secreting eosinophil
hematopoiesis
Clonal T Cells No T-Cell Clone

28. HES Subtypes in a Retrospective Cohort
Klion AD. Blood. 2015;126(9):1069-1077.
26%
12%
32%
11%
12%
1% 4%
6%
Distribution of HES Diagnoses (n = 303)
Overlap Associated Idiopathic HES MHES
LHES Familial HEUS Other
26%
34%
7%
9%
23% Neoplasm
Helminth
Drug
Immunodeficiency
Other
Distribution of Associated HES

29. Myeloproliferative HES (M-HES)
• HES with documented or presumed clonal eosinophilic involvement
Definition
• PDGFR and FGFR1 rearrangements
• JAK2 genetic alterations
• Chronic eosinophilic leukemia
Examples
• Male predominance in PDGFR-associated MPN
• High mortality if untreated
• Frequently elevated serum tryptase and vitamin B12 levels
Features
1. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.
2. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.

30. Lymphocytic HES (L-HES)
•HES with a clonal or phenotypically abnormal lymphocyte population that produces cytokines (particularly IL-5) and
drives eosinophilia
Definition
•CD3-/CD4+ L-HES
•Episodic eosinophilia/angioedema (Gleich’s syndrome)
Examples
•Equally common in men and women
•High rate of skin and soft tissue complications
•Elevated level of IgE and CCL-17
•Progression to lymphoma in 5% to 25% of patients
Features
1. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.
2. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.

31. Overlap HES
• Eosinophilic manifestations restricted to single organ system with peripheral eosinophilia >1500/mm3
Definition
• Eosinophilic granulomatosis with polyangiitis (EGPA)—special category of overlap HES because the
underlying pathophysiology is related to eosinophilic infiltration of the blood vessels, which leads to
multisystem complications
• Eosinophilic gastrointestinal disorders (eg, eosinophilic esophagitis)
Examples
• May be challenging to distinguish from idiopathic HES when AEC is elevated
Features
1. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.
2. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.

32. Undefined HES
1. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97.
2. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.
• HES of unknown cause that does not meet criteria for any of
the other categories
Definition
• Multisystem involvement common
• Most common category
Features

33. Secondary Causes of Hypereosinophilia
Category Examples (not inclusive)
Allergic disorders Asthma, atopic dermatitis, allergic rhinitis, allergic bronchopulmonary aspergillosis
Drug hypersensitivity Penicillins, antiepileptics (phenytoin, valproate), antidepressants, antihypertensives (ACEis, β-blockers)
Infection
Helminthic Strongyloidiasis, trichinellosis, filariasis, schistosomiasis, hookworm
Ectoparasitic Scabies, myiasis
Protozoan Isosporiasis, sarcocystis myositis
Fungal Coccidiomycosis, allergic bronchopulmonary aspergillosis, histoplasmosis
Viral HIV, HTLV
Hematologic/neoplastic
disorders
Leukemia, lymphoma, adenocarcinoma, squamous cell carcinoma, systemic mastocytosis
Immunologic disorders
Immunodeficiency DOCK8 deficiency, hyper-IgE syndrome, Omenn’s syndrome
Autoimmune and idiopathic Sarcoidosis, IBD, IgG4 disease, other CTDs
Miscellaneous Radiation exposure, cholesterol emboli, adrenal insufficiency, eosinophilic GI disorders
ACEi, angiotensin-converting enzyme inhibitor; CTD, connective tissue disease; HTLV, human T-cell leukemia virus; IBD, inflammatory bowel
disease.
1. Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.
2. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.

34. Differential Diagnosis and Exclusion of Secondary
Causes
Evaluation for drug hypersensitivity reactions
• Caused by a long list of agents
• Discontinue nonessential pharmacotherapies before diagnosis
Evaluation for parasitic infections
• Dictated by exposure history & clinical signs and symptoms, with the
exception of strongyloidiasis (asymptomatic)
Evaluation for neoplasms
• Eosinophilia can precede symptoms of neoplasms by several years
Klion AD. Blood. 2009;114(18):3736-3741.

35. Recommended Evaluation According to End-Organ
Complications and/or Laboratory Abnormalities
Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.
• CBC with differential
• Peripheral smear
• Flow cytometry
• Serum tryptase
• Stool ova and parasites
• ANCA
• Serum B12 level
• HIV serologies
• Serum IgE
• Strongyloides IgG
• ESR/CRP
• ANA
General evaluation
Cardiac
• Serum troponin T
• ECG
• Echocardiogram
Gastrointestinal
• Liver enzymes
Pulmonary
• Pulmonary function tests
• Chest X-ray
Renal
• Blood urea
nitrogen/creatinine
• Urinalysis
Screening for end-organ involvement

36. Recommended Evaluation According to End-Organ
Complications and/or Laboratory Abnormalities
Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251.
• CBC with differential
• Peripheral smear
• Flow cytometry
• Serum tryptase
• Stool ova and parasites
• ANCA
• Serum B12 level
• HIV serologies
• Serum IgE
• Strongyloides IgG
• ESR/CRP
• ANA
General evaluation
Cardiac
• Serum troponin T
• ECG
• Echocardiogram
Gastrointestinal
• Liver enzymes
Pulmonary
• Pulmonary function tests
• Chest X-ray
Renal
• Blood urea
nitrogen/creatinine
• Urinalysis
Screening for end-organ involvement
Prominent end-
organ
symptoms or
lab/imaging
abnormalities?
Cardiac
• Cardiac MRI
• Endomyocardial biopsy
Hematologic
• Bone marrow biopsy
• Chest/abdomen/pelvis CT
• Peripheral FISH/RT-PCR for
FIP1L1-PDGFRA
Pulmonary
• Bronchoalveolar lavage
• Lung biopsy
• Chest CT
Neurologic
• Brain MRI or head CT with
contrast
• Electroencephalogram
• Nerve conduction studies
Vascular
• Angiography
Dermatologic
• Skin biopsy
Renal
• Kidney biopsy
Gastrointestinal
• Endoscopy with
biopsies
• Abdominal CT scan
• Amylase/lipase

37. Summary
• HES is characterized by hypereosinophilia (tissue or blood), clinical
symptoms and end-organ involvement, and the absence of other
diagnoses
• Dermatologic, pulmonary, and GI manifestations are common clinical
presentations of HES
• HES can cause irreversible cardiovascular complications when left
untreated

38. Treating Hypereosinophilic
Syndromes

39. Overview of HES Treatment
• Acute treatment
• HES treatment regimens
• Conventional treatments
• Novel and emerging treatments
• Anti-IL-5 therapy

40. Initial Approach to HES Treatment
• Severity and type of presentation guide treatment decision making
• With life-threatening HES, promptly initiate high-dose
glucocorticoids
• Limited diagnostic evaluations prior to treatment to identify candidates for
alternative therapies
• Steroids should not be withheld when symptoms are rapidly progressing
Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.

41. Initial Treatment Regimens
• High-dose glucocorticoids (prednisone 1 mg/kg/d) are the initial
treatment of choice
• Consider empiric ivermectin (200 µg/kg orally for 2 days) for any patient with
potential exposure to Strongyloides
• Intravenous glucocorticoids for those who are acutely ill or with GI
involvement that could impair absorption
Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.

42. Biomarkers Predicting HES Progression Are Lacking, But Risk
Factors for Poor Outcomes Have Been Identified
Pardanani A, et al. Leukemia. 2016;30(9):1924-1926.s
Features Evaluated for
High-Risk HES
• Hepatosplenomegaly
• Age >60 years
• Hemoglobin <10 g/dL or cardiac
involvement
Survival According to HES in a Retrospective Cohort (n = 98)
Potential indicators of m-HES
• Elevated vitamin B12 levels
• Elevated tryptase levels
1
0.8
0.6
0.4
1
0.2
0 50 100 150 200 250 300 350
Follow-up (months)
Survival
probability
Low-risk, 60 patients, 3 events, 5-year survival rate 98%
High-risk, 38 patients, 14 events, 5-year survival rate 62%
P < .0001

43. Conventional Second-Line Treatments for HES
Drug Dosing Common adverse events Notes
PDGFR-associated myeloproliferative HES
Imatinib 100-400 mg PO
Cytopenias, hepatitis, diarrhea, edema,
necrotizing myocarditis
• First-line for PDGFR-associated myeloid
neoplasms
• Second-line for other forms of myeloid HES
Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.

44. Conventional Second-Line Treatments for HES
Drug Dosing Common adverse events Notes
PDGFR-associated myeloproliferative HES
Imatinib 100-400 mg PO
Cytopenias, hepatitis, diarrhea, edema,
necrotizing myocarditis
• First-line for PDGFR-associated myeloid
neoplasms
• Second-line for other forms of myeloid HES
PDGFR-negative HES
Prednisone Varies, PO or IV
Weight gain, osteopenia, diabetes, mood
disturbance
• First-line for PDGFR-negative myeloid HES
• Adjunct for PDGFR-positive with cardiac
involvement
Hydroxyurea 1-2 g PO Cytopenias, diarrhea
• Second-line for idiopathic HES and PDGFR-
negative myeloid HES
• Low dose may potentiate interferon-ɑ
Interferon-ɑ
Varies, 1-3 mU SC daily
or 3 times per week
Flu-like symptoms, depression, cytopenias,
hypothyroidism, neuropathy, liver toxicity
• Second-line for all forms of HES
• Preferred second-line for lymphocytic HES
Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.

45. Conventional Second-Line Treatments for HES
Drug Dosing Common adverse events Notes
PDGFR-associated myeloproliferative HES
Imatinib 100-400 mg PO
Cytopenias, hepatitis, diarrhea, edema,
necrotizing myocarditis
• First-line for PDGFR-associated myeloid
neoplasms
• Second-line for other forms of myeloid HES
PDGFR-negative HES
Prednisone Varies, PO or IV
Weight gain, osteopenia, diabetes, mood
disturbance
• First-line for PDGFR-negative myeloid HES
• Adjunct for PDGFR-positive with cardiac
involvement
Hydroxyurea 1-2 g PO Cytopenias, diarrhea
• Second-line for idiopathic HES and PDGFR-
negative myeloid HES
• Low dose may potentiate interferon-ɑ
Interferon-ɑ
Varies, 1-3 mU SC daily
or 3 times per week
Flu-like symptoms, depression, cytopenias,
hypothyroidism, neuropathy, liver toxicity
• Second-line for all forms of HES
• Preferred second-line for lymphocytic HES
Methotrexate
7.5-20 mg weekly, PO or
SC
Cytopenias, liver toxicity, pneumonitis,
skin rash, encephalopathy, malignancy
• Alternative second-line for EGPA and HES with
pulmonary involvement
Cyclosporine 150 mg PO
Nephrotoxicity, hypertension,
neurotoxicity, malignancy
• Anecdotal reports of efficacy for lymphocytic
HES
Klion A. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331.

46. Novel Treatment Options Have Been Developed
That Target Distinct Eosinophil Pathways
1. Stella S, et al. Int J Mol Sci. 2021;22(2):486.
2. Harish A, et al. Clinic Rev Allerg Immunol. 2020;59:231-247.
Image courtesy of Stella S et al. Int J
Mol Sci. 2021;22(2):486. CC BY 4.0.
• Tyrosine kinase inhibitors and
monoclonal antibodies used in other
inflammatory conditions
• Targeted therapies may have:
• More specificity
• Lower rates of AEs
Imatinib
Nilotinib
Sorafenib
Prednisone
Hydroxyurea
IFN-ɑ
Dexpramipexole
Benralizumab
Sorafenib
Pemigatinib
Ruxolitinib Venetoclax +
azacytidine or
pevonedistat
Mepolizumab
Reslizumab
Alemtuzumab
Omalizumab

47. IL-5-Targeted Novel Treatment Options for HES
Stella S, et al. Int J Mol Sci. 2021;22(2):486.
Drug
Mechanism of
action
Indications Use in HES Dosing
Anti-IL-5/IL-5R
Mepolizumab
Inhibit IL-5 binding to
receptor
Indicated for eosinophilic
asthma, EGPA, and HES
Indicated for eosinophilic asthma, EGPA,
and HES
100-300 mg
Q4W
Benralizumab
Inhibit
oligomerization of
the IL-5R subunits
Indicated for severe asthma Phase 3 ongoing for HES
30 mg SC
Q4W
Reslizumab
Inhibit eosinophil
proliferation by
binding to IL-5R
Indicated for eosinophilic
asthma
Indicated for eosinophilic asthma 1 mg/kg

48. Other Monoclonal Antibodies for HES
1. Stella S, et al. Int J Mol Sci. 2021;22(2):486.
2. Dellon ES, et al. N Engl J Med. 2020;383(17):1624-1634.
Drug
Mechanism of
action
Indications Use in HES Dosing
Anti-IgE
Omalizumab
Inhibit release of
cytokines (IL-4, IL-5, and
IL-13)
Indicated for allergic asthma,
nasal polyps, and idiopathic
urticaria
Indicated for allergic asthma
Based on
weight per
serum IgE
Anti-CD52
Alemtuzumab
Mediate lysis of CD52+
cells
Indicated for relapsing forms of
MS
May be considered off-label for those with
refractory HES
5-30 mg 1-3
times weekly
Anti-Siglec-8
Lirentelimab
Deplete eosinophils and
inhibit mast cells
No indications
Phase 2 positive for eosinophilic gastritis
and duodenitis
20 mg PO
BID

49. Small Molecules for HES
Stella S, et al. Int J Mol Sci. 2021;22(2):486.
Drug
Mechanism of
action
Indications Use in HES Dosing
JAK-STAT inhibitor
Ruxolitinib
Inhibit dysregulated
JAK-STAT signaling
Indicated for myelofibrosis Phase 2 ongoing for HES
20 mg PO
BID
TKI
Sorafenib
Inhibit kinases involved
in tumor cell
proliferation and
angiogenesis
Indicated for uHCC, aRCC, and
refractory DTC
May be considered off-label for patients
with FLT3- or PDGFR-rearranged cases
400 mg PO
BID
Other small molecule
Dexpramipexole Unknown No indications
Phase 2 results positive for eosinophilic
asthma
75-300 mg
PO

50. Mepolizumab in Patients With HES (Phase 3)
Roufosse F, et al. J Allergy Clin Immunol. 2020;146(6):1397-1405. Permission granted for this non-
commercial use. https://creativecommons.org/licenses/by-nc-nd/4.0/.
Efficacy in Patients With HES
Cumulative
number
of
flares
Probability
of
flare
• 108 participants with PDGFRA-negative HES (AEC
≥1000/mm3) who experienced ≥2 flares in the past year
• Primary end point: proportion of patients with a flare during
the study
• Mepolizumab significantly decreased the risk for flares
(28% vs 56%; P = .002)

51. Mepolizumab in Patients With EGPA (Phase 3)
From Mass. Med. Society, Michael E. Wechsler, Praveen Akuthota, David Jayne, et al, "Mepolizumab or Placebo for
Eosinophilic Granulomatosis with Polyangiitis", Volume No., 376(20):1921-1932 Copyright ©2017 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society license 5051021116509.
Efficacy in Patients With EGPA
Participants
With
Remission
Participants
With
Relapse
• 136 participants with refractory EGPA receiving prednisolone
were randomized to mepolizumab or placebo
• Significantly increased accrued remission over 1 year (28% vs
0.3% with ≥24 weeks of remission; OR, 5.91; P < .001)
• Remission: 53% vs 19% (mepolizumab vs placebo,
respectively)

52. Benralizumab in Patients With HES (Phase 2)
From N Engl J Med, Kuang FL, et al, “Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome.” ,
2019;380(14):1336-1346. Copyright © 2019; Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society-#5051021377760
• 20 symptomatic participants
with PDGFRA-negative HES (AEC
≥1000/mm3)
• AEC was reduced by 50% in 90%
of patients treated with
benralizumab and 30% treated
with placebo (P = .02)
• During the open-label period,
89% of participants had clinical
and hematologic responses

53. IL-5 Therapies: Common Adverse Events
• Anti-IL-5 and –IL-5R therapies have been shown to be relatively well
tolerated
• Common AEs include nasopharyngitis, injection-site reactions,
headache, and upper respiratory tract infections
• Serious AEs are rare and include asthma worsening, anaphylactic
reactions, and pneumonia
Bagnasco D, et al. Biomed Res Int. 2018;2018:5698212.

54. Khoury P, Bochner BS. J Allergy Clin Immunol Pract. 2018;6(5):1446-1453.
Eosinophilia
Review and verify
Determine:
• Onset
• Magnitude
Temporal association of:
• Exposures
• Medications
• Symptoms
History
Comorbid conditions
Exposures
Medications
Endemicity
Travel
Other infections
Physical exam
Nasal/sinus disease or
polyps
Mucosal ulcers
Adventitious lung sounds
Heart murmurs or rubs
Lymphadenopathy
Abdominal tenderness
Liver/spleen enlargement
Joint/muscle abnormality
Skin rashes or edema
Neuropathy or weakness
At presentation
Laboratory testing
CBC with differential
Liver/kidney tests
Troponin
LDH
Stool/serology for parasites
Diagnostic testing
ECG/echocardiogram
Pulmonary function testing
Autoantibody testing
CT scans
Biopsies (if applicable)
Initial diagnostic work-up
1
Workup and manage
abnormal findings:
Cardiac MRI
Endoscopy/colonoscopy
EMG/NCV
MRI of affected organs
Stop culprit medications
Treat parasitic infections
Subsequent diagnostic work-
up
2
Alternative diagnoses
Atopic conditions
Autoimmune conditions
Drug hypersensitivity
Malignancy
Parasitic infections
Immunodeficiency
Treat or refer accordingly
Continued diagnostic work-up:
Peripheral smear
Serum tryptase and vitamin B12
T-cell clonality
Genetic and molecular testing
Flow cytometry
Genetic or immunodeficiency workup
Bone marrow biopsy or hematology referral
Urgent treatment required due to end-organ
dysfunction or severe complications
Initiate high-dose glucocorticoids and/or other
therapies while continuing workup
Continued
workup
reveals
alternative
diagnoses or
more specific
HES subtype
Summary: HES Diagnosis and Treatment

55. Khoury P, Bochner BS. J Allergy Clin Immunol Pract. 2018;6(5):1446-1453.
Alternative diagnoses
Atopic conditions
Autoimmune conditions
Drug hypersensitivity
Malignancy
Parasitic infections
Immunodeficiency
Treat or refer accordingly
Continued diagnostic work-up:
Peripheral smear
Serum tryptase and vitamin B12
T-cell clonality
Genetic and molecular testing
Flow cytometry
Genetic or immunodeficiency workup
Bone marrow biopsy or hematology referral
Urgent treatment required due to end-organ
dysfunction or severe complications
Initiate high-dose glucocorticoids and/or other
therapies while continuing workup
Continued
workup
reveals
alternative
diagnoses or
more specific
HES subtype
Summary: HES Diagnosis and Treatment
Lymphoid HES
Glucocorticoids
Immunosuppressives
Interferon-ɑ
Biologic therapy
JAK-STAT inhibitors
Idiopathic HES
Glucocorticoids
Interferon-ɑ
Hydroxyurea
Biologic therapy
Immunosuppressives
Myeloid HES
Glucocorticoids (limited
benefit)
Imatinib
2nd-generation TKIs
JAK-STAT inhibitors
Overlap HES
Glucocorticoids
Dietary therapy
Mepolizumab
Immunosuppressives
Consider clinical trials if
appropriate
Treatment
by
HES
subtype
Eosinophilia
Review and verify
Determine:
• Onset
• Magnitude
Temporal association of:
• Exposures
• Medications
• Symptoms
History
Comorbid conditions
Exposures
Medications
Endemicity
Travel
Other infections
Physical exam
Nasal/sinus disease or
polyps
Mucosal ulcers
Adventitious lung sounds
Heart murmurs or rubs
Lymphadenopathy
Abdominal tenderness
Liver/spleen enlargement
Joint/muscle abnormality
Skin rashes or edema
Neuropathy or weakness
At presentation
Laboratory testing
CBC with differential
Liver/kidney tests
Troponin
LDH
Stool/serology for parasites
Diagnostic testing
ECG/echocardiogram
Pulmonary function testing
Autoantibody testing
CT scans
Biopsies (if applicable)
Initial diagnostic work-up
1
Workup and manage
abnormal findings:
Cardiac MRI
Endoscopy/colonoscopy
EMG/NCV
MRI of affected organs
Stop culprit medications
Treat parasitic infections
Subsequent diagnostic work-
up
2
3

56. Summary
• Prompt treatment with glucocorticoids is recommended for those
with life-threatening symptoms
• Treatments should be individualized by HES classification
• Consider biologic or small-molecule therapy for candidate patients to
reduce flares

57. Case Study

58. Overview of HES Case Study
• HES laboratory work-up
• Differential diagnosis
• Initial treatment
• Treatment modifications

59. Case Study: Jonathan
• 62-year-old male
• Presents to PCP with rash on chest
and right arm
Image courtesy of DermNetNZ.org. https://dermnetnz.org/topics/hypereosinophilic-syndrome/. CC BY-NC-
ND 3.0 NZ.

60. Case Study: Jonathan
• On questioning, the patient also notes fatigue
and shortness of breath
• Medical history:
• Hypercholesterolemia diagnosed at age 52 years
(controlled with moderate-dose statin)

61. Case Study: Jonathan
• CBC results:
• Absolute eosinophil count 2800/mm3 (33%)
• Normal hemoglobin and platelets
• Normal comprehensive metabolic panel

62. Case Study: Jonathan
• CBC results:
• Absolute eosinophil count 2800/mm3 (33%)
• Normal hemoglobin and platelets
• Normal comprehensive metabolic panel
• Rash and hypereosinophilia persist when
medications are discontinued

63. Case Study: Jonathan
• CBC results:
• Absolute eosinophil count 2800/mm3 (33%)
• Normal hemoglobin and platelets
• Normal comprehensive metabolic panel
• Rash and hypereosinophilia persist when
medications are discontinued
• PCP refers Jonathan to allergy/immunology

64. Case Study: Jonathan
• CBC results:
• Absolute eosinophil count 2800/mm3 (33%)
• Normal hemoglobin and platelets
• Normal comprehensive metabolic panel
• Rash and hypereosinophilia persist when
medications are discontinued
• PCP refers Jonathan to allergy/immunology
What testing should be ordered for this
patient?

65. Case Study: Jonathan
Based on suspicion of HES, additional testing:
• Laboratory testing: serum immunoglobulin levels,
troponin, tryptase, B12, HIV, ANCA, stool or
serology for parasitic infections, lymphocyte
phenotyping by flow cytometry
• Imaging: chest/abdomen/pelvis CT,
echocardiogram
• Bone marrow biopsy, including cytogenetics
• Biopsy of rash

66. Case Study: Jonathan
Based on suspicion of HES, additional testing:
• Laboratory testing: serum immunoglobulin levels,
troponin, tryptase, B12, HIV, ANCA, stool or
serology for parasitic infections, lymphocyte
phenotyping by flow cytometry
• Imaging: chest/abdomen/pelvis CT,
echocardiogram
• Bone marrow biopsy, including cytogenetics
• Biopsy of rash
While awaiting test results, should immediate
treatment with glucocorticoids be considered
for this patient?

67. Case Study: Jonathan
• Treatment with glucocorticoids not initiated
immediately
• Presentation not life-threatening

68. Case Study: Jonathan
• Notable results
• Bone marrow biopsy: eosinophil precursors
• Rash biopsy: eosinophil infiltration
• Rest of test results negative or within normal
limits

69. Case Study: Jonathan
• Notable results
• Bone marrow biopsy: eosinophil precursors
• Rash biopsy: eosinophil infiltration
• Rest of test results negative or within normal
limits
What diagnosis would you consider for this
patient?

70. Case Study: Jonathan
• Jonathan is diagnosed with undefined HES

71. Case Study: Jonathan
• Jonathan is diagnosed with undefined HES
What first-line treatment should be considered
for this patient?

72. Case Study: Johnathan
Initial treatment:
• Prednisone 60 mg/day initiated

73. Case Study: Johnathan
• Patient returned 6 weeks later
• Was not able to taper below 20 mg/day
(symptoms worsened, hypereosinophilia
persisted)

74. Case Study: Johnathan
Treatment adjustments:
• Continue prednisone
• Add anti-IL-5 therapy

75. Case Study: Johnathan
• 2 months later, Jonathan is able to successfully
taper off steroids
• Rash resolved
• Eosinophil count 100/mm3
• No shortness of breath
• Chest X-ray clear

76. Case Study: Johnathan
• At 1 year follow-up, the patient reports that he
is feeling well and symptoms have not
returned
• He has not had any flares

77. Summary
• HES is characterized by hypereosinophilia (tissue or blood), clinical
symptoms and end-organ involvement, and the absence of other
diagnoses
• Rash, fatigue, and other systemic symptoms often accompany HES
• Consider step-up with biologic therapy for patients who cannot taper
corticosteroids