65 Eosinophils and Their Disorders

Question 1

Most specific eosinophilopoietic growth factor

Answer 1

IL-5

Question 2

Eosinophils persist in the circulation for ______ hours

Answer 2

25 hours

Question 3

Granular proteins uniquely expressed by eosinophils

Answer 3

EPX and MBP-2

Question 4

Majority of mature eosinophilic granules are

Answer 4

Secondary (specific) large granules

Question 5

The smaller primary granules of eosinophils contain

Answer 5

Charcot-Leyden Crystal protein (Galectin-10)

Question 6

Cell surface markers of eosinophils using flow cytometry

Answer 6

EMR-1, Siglec-8, and CCR3 (CD193)

Question 7

In tissues, eosinophils can be detected by immunohistochemistry using

Answer 7

MBP, ECP, and EPX stains

Question 8

Eosinophilia is defined as

Answer 8

Exceeding the upper limit of normal and an absolute eosinophil count (AEC) of 0.35–0.5 ×10 9 /L

Question 8

Severity of eosinophilia

Answer 8

Mild (AEC <1.5 ×10 9 /L)
Moderate or marked (AEC 1.5–5 × 10 9 /L)
Severe or massive (AEC >5 × 10 9 /L)

Question 9

Hypereosinophilia (HE) is defined as

Answer 9

Persistent eosinophilia greater than 1.5 × 10 9 /L

Divided into primary (clonal or neoplastic), secondary (reactive), hereditary (familial), or HE of undetermined significance

Question 10

Hypereosinophilic syndrome (HES)

Answer 10

(a) a persistent eosinophilia of greater than 1.5× 10 9 /L for longer than 6 months or death before 6 months associated with the signs and symptoms of hypereosinophilic disease

(b) a lack of evidence for parasitic, allergic, or other known causes of eosinophilia; and

(c) presumptive signs and symptoms of organ involvement

Question 11

Idiopathic HE or HE of undetermined significance

Answer 11

Patients with an absolute eosinophil greater than 1.5 × 10 9 /L are asymptomatic with no end-organ damage

Question 12

Gene rearrangement associated with myeloid/lymphoid neoplasms with eosinophilia

Answer 12

PDGFRA, PDGFRB, and fibroblast growth factor receptor (FGFR) 1, PCM1-JAK2

Question 13

Incidence of FIP1L1–PDGFRA fusion with idiopathic HE or HES

Answer 13

10%

Question 14

Most common clinical manifestations at presentation of HES

Answer 14

Skin (37%)
Lungs (25%)
GI tract (14%)

At table: Hematopoetic, heart, skin, nervous system

Question 15

Rare HES-like hereditary immune deficiencies characterized by an elevated IgE level, eczema-like skin rashes, characteristic facial and dental abnormalities, and recurrent infections

Answer 15

Hyper IgE syndromes

Question 16

Mutations in Hyper IgE syndromes

Answer 16

Autosomal dominant mutations- STAT3 (Job syndrome)

Autosomal recessive mutations- DOCK8, PGM3, SPINK5, or TYK2

Question 17

An elevated serum vitamin B12 level is commonly seen in primary HES/CEL, NOS, caused by __________

Answer 17

Increased production of the haptocorrins

Question 18

Useful screening test in patients with HE

Answer 18

Tryptase

Question 19

Useful in the diagnosis of lymphocyte-variant HE/HES

Answer 19

Testing for clonal T lymphocytes by flow cytometry and polymerase chain reaction (PCR)/next-generation sequencing (NGS)

Question 20

TRUE OR FALSE

Given its dire consequences, all patients with HE and HES should be screened for cardiac involvement with troponin (T or I) looking for myocarditis and an echocardiogram (+/- N-terminal pro B-type natriuretic peptide [NT-BNP]) to evaluate the presence of cardiomyopathy.

Answer 20

TRUE

Question 21

In using FISH in the diagnosis of primary HES, this is a surrogate for FIP1L1-PDGFRA fusion gene

Answer 21

CHIC2 deletion

Interstitial submicroscopic microdeletion on the long arm of chromosome 4

Question 22

Immunohistochemical staining to identify increased numbers of neoplastic mast cells

Answer 22

CD117, tryptase, and CD25

Question 23

Translocations that warrants FISH testing for PDGFRA, PDGFRB, FGFR1, JAK2, or FLT3

Answer 23

4q12, 5q31~33, 8p11~12, 9p24, or 13q12

Question 24

In patients with elevated tryptase, testing should be undertaken for________

Answer 24

KIT D816V mutation

Question 25

Most common gene partner of: PDGFRA: _________ PDGFRB: _________ FGFR1: __________ JAK2: _________ ABL1: _________ FLT3: _________

Answer 25

PDGFRA: FIP1L1 PDGFRB: ETV6 FGFR1: ZMYM2 JAK2: PCM1 ABL1: ETV6 FLT3: ETV6

Question 26

There is a remarkable ________ predominance in patients with FIP1L1PDGFRA, PDGFRB, and JAK2 fusions for unknown reason

Answer 26

male predominance

Question 27

Treatment of choice for patients with PDGFRA and PDGFRB rearrangements

Answer 27

**Imatinib** PDGFRA: starting dose of **100 mg/day** with dose increase to 400 mg PDGFRB: initially with **400 mg/day**, and the dose is then lowered to 100 mg/day

Question 28

TRUE OR FALSE Higher standard doses of imatinib being required for patients with PDGFRA and PDGFRB rearrangements than patients with CML

Answer 28

FALSE ## Footnote **LOWER** standard doses of imatinib being required for patients with PDGFRA and PDGFRB rearrangements than patients with CML who present with chronic phase disease since in vitro, PDGFRA and PDGFRB rearrangements are **MORE SENSITIVE to imatinib** compared with BCR-ABL1

Question 29

Drug added to Imatinib to **dampen the immune response** and **lessen the risk of myocardial injury** from degranulation of eosinophils

Answer 29

Prophylactic **glucocorticoids** during the initial **1 to 2 weeks** of imatinib therapy

Question 30

Most common mutation in patients with primary or secondary resistance to imatinib in patients with PDGFRA/PDGFRB rearrangements

Answer 30

**T674I** (most commonly) and D842V

Question 31

TKI with partial activity against the **FGFR1** tyrosine kinase

Answer 31

Ponatinib

Question 32

FGFR1 inhibitor

Answer 32

Pemigatinib

Question 33

TRUE OR FALSE AHSCT is recommended following TKI inhibition in PDGFRA and PDGFRB

Answer 33

FALSE

Question 34

This fusion gene is cryptic and not detected by routine cytogenetics unless alternatve gene partners present

Answer 34

FIP1L1

Question 35

Preferred or Potential TKI in JAK2

Answer 35

Ruxolitinib

Question 36

Preferred or Potential TKI in ABL1

Answer 36

Imatinib Nilotinib Dasatinib

Question 37

Preferred or Potential TKI in FLT3

Answer 37

Sorafenib Sunitinib Midostaurin Second generation FLT3 inhibitors

Question 38

HE with concomitant evidence of a clonal cytogenetic or molecular abnormality OR An increase in myeloblast percentage in the marrow or blood (≥5% and 2%, respectively but <20% to exclude acute leukemia)

Answer 38

CHRONIC EOSINOPHILIC LEUKEMIA, NOT OTHERWISE SPECIFIED

Question 39

Treatment options for CEL, NOS

Answer 39

Hydroxyurea Interferon (INF)-α Imatinib Allogeneic HSCT

Question 40

Flow immunophenotypic abnormalities in lymphocyte variant HE or HES

Answer 40

**Absence of CD3** from the T-cell receptor complex **(CD3 CD4+)** **Double-negative immature T cells (CD3+ CD4– CD8–)** **CD3+ CD4+ CD7–**

Question 41

Patients with lymphocyte variant HE or HES are at a slightly increased risk of _______________

Answer 41

Lymphomas, mainly **T-cell lymphoma and Sézary syndrome**

Question 42

Treatment for lymphocyte variant HE or HES

Answer 42

**Glucocorticoids** ## Footnote Glucocorticoid-sparing agent such as **INF-α, cyclosporine**, or **anti–IL-5–directed therapy**

Question 43

A humanized monoclonal IgG1 antibody that binds free IL-5

Answer 43

Mepolizumab

Question 44

A humanized afucosylated monoclonal antibody against the IL-5Rα chain

Answer 44

Benralizumab

Question 45

Mainstay of treatment for idiopathic HES

Answer 45

Glucocorticoids

Question 46

Mainstay of treatment for organ-restricted HES

Answer 46

Glucocorticoids

Question 46

Treatment for eosinophilic asthma

Answer 46

**Mepolizumab** (100 mg subcutaneously every 4 weeks) **Reslizumab** (anti–IL-5 antibody dosed at 3 mg/kg intravenously every 4 weeks) **Benralizumab** (30 mg subcutaneously every 4 weeks)

Question 47

Treatment for eosinophilic esophagitis

Answer 47

Reslizumab

Question 48

TRUE OR FALSE Eosinophilia can be seen in patients with several WHO-defined myeloid and lymphoid neoplasms, but it is common to have eosinophil-mediated organ damage in these patients.

Answer 48

FALSE Eosinophilia can be seen in patients with several WHO-defined myeloid and lymphoid neoplasms, but it is UNCOMMON to have eosinophil-mediated organ damage in these patients.

Question 49

Mutation in AML with increased marrow eosinophils

Answer 49

Core binding factor (CBF)

Question 50

In MDS patients, eosinophilia greater than ___________ predicts significantly reduced survival and marrow eosinophilia is associated with complex karyotype

Answer 50

0.35 × 10 9 /L

Question 51

TRUE OR FALSE The presence of eosinophilia in MDS and SM carries prognostic significance

Answer 51

TRUE The presence of eosinophilia in MDS and SM carries prognostic significance

Question 52

Rare disease characterized by **cyclic eosinophilia**, **angioedema, fever, weight gain, polyclonal IgM**, and **aberrant CD3 - clonal T cells** that occur every 3–4 weeks and self-resolves with spontaneous diuresis

Answer 52

Gleich syndrome

Question 53

Rare benign chronic inflammatory disease characterized by **lymphadenopathy, elevated IgE levels,** and **eosinophilia**

Answer 53

Kimura disease

Question 54

Toxic oil:________ Eosinophilia–myalgia syndromes: __________

Answer 54

Toxic oil:contaminated rapeseed oil Eosinophilia–myalgia syndromes: tryptophan supplements

Question 55

Mature eosinophils are normally present in the gastrointestinal (GI) tract except in the

Answer 55

Esophagus

Question 56

Eosinophil's granular contents

Answer 56

Proteins (eg, major basic proteins [MBP], eosinophil peroxidase [EPX], eosinophil cationic protein [ECP], and eosinophil derived neurotoxin) Enzymes (eg, nonspecific esterase and catalase) Inflammatory mediators/cytokines (eg, eotaxin, ILs, and leukotriene C4)

Question 57

TRUE OR FALSE The workup of patients presenting with HE starts with excluding secondary (reactive) causes and screening for end-organ involvement

Answer 57

TRUE The workup of patients presenting with HE starts with excluding secondary (reactive) causes and screening for end-organ involvement

Question 58

TRUE OR FALSE Elevated immunoglobulin (Ig) E levels is a nonspecific finding that is mostly seen in reactive conditions (infectious, allergic, vasculitis, and lymphocytevariant HES)

Answer 58

TRUE Elevated immunoglobulin (Ig) E levels is a nonspecific finding that is mostly seen in reactive conditions (infectious, allergic, vasculitis, and lymphocytevariant HES) But its elevation is variable in patients with primary HES/CEL, NOS

Question 59

Patients with neurologic symptoms should undergo brain imaging (with or without cerebral angiography), with preference for

Answer 59

Magnetic resonance imaging

Question 60

Mixed lineage (eg, undifferentiated or biphenotypic leukemia) presentation is more common with ____________ fusions

Answer 60

FGFR1 fusions

Question 61

TRUE OR FALSE The presence of T-cell receptor rearrangements without phenotypic abnormality on flow cytometry is not considered sufficient for the diagnosis of lymphocyte-variant HES and should be interpreted with caution

Answer 61

TRUE The presence of T-cell receptor rearrangements without phenotypic abnormality on flow cytometry is not considered sufficient for the diagnosis of lymphocyte-variant HES and should be interpreted with caution

Question 62

TRUE OR FALSE Patients with idiopathic HES who have marrow findings similar to CEL, NOS (discussed earlier) but do not meet its diagnostic criteria have a worse prognosis than those without such marrow abnormalities

Answer 62

TRUE Patients with idiopathic HES who have marrow findings similar to CEL, NOS (discussed earlier) but do not meet its diagnostic criteria have a worse prognosis than those without such marrow abnormalities

Question 63

In patients presenting with eosinophilic fasciitis, evaluation of underlying_______ is recommended.

Answer 63

MDS

Question 64

TRUE OR FALSE Acute and chronic graft-versus-host disease can present with eosinophilia and is probably a poor prognostic biomarker in these patients

Answer 64

FALSE Acute and chronic graft-versus-host disease can present with **eosinophilia** and is probably a **good prognostic biomarker** in these patients