Received: 2 August 2017 | Accepted: 3 August 2017

DOI: 10.1002/ajh.24880

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL A JH

MALIGNANCIES

World Health Organization-defined eosinophilic disorders: 2017

update on diagnosis, risk stratification, and management

Jason Gotlib

Stanford Cancer Institute, Stanford,

California 94305-5821
Correspondence
Jason Gotlib, Stanford Cancer Institute, 875
Blake Wilbur Drive, Room 2324, Stanford,
CA 94305-5821.
Email: jason.gotlib@stanford.edu
Abstract
Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or
reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.
Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count
greater than 1500/mm3 and may be associated with tissue damage. After exclusion of secondary
causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of
morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridiza-
tion, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal
evidence for an acute or chronic myeloid or lymphoproliferative disorder.

Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evalu-
ation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-
molecular classification scheme of disease subtypes which includes the major category “myeloid/
lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with
PCM1-JAK2,” and the “MPN subtype, chronic eosinophilic leukemia, not otherwise specified” (CEL,
NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosino-
phila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.

Risk-adapted therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For
patients with milder forms of eosinophilia (e.g., < 1500/mm3) without symptoms or signs of organ
involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of
rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these dis-
eases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant
hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as ini-
tial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line
cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive
forms of HES and CEL with outcomes reported for limited numbers of patients. The use of anti-
bodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52
(alemtuzumab), as well as other targets on eosinophils remains an active area of investigation.

1 | DISEASE OVERVIEW
1.1 | Epidemiology
The incidence and prevalence of HES is not well characterized. Using
the International Classification of Disease for Oncology (version 3), and
coding of 9964/3 (HES including chronic eosinophilic leukemia), the
Surveillance, Epidemiology and End Results (SEER) database from 2001
to 2005 revealed that the age-adjusted incidence rate was approxi-
mately 0.036 per 100 000.1 The incidence of eosinophilias with recur-
rent genetic abnormalities (PDGFRA/B, FGFR1) comprises a minority of
these patients. The median frequency of the FIP1L1-PDGFRA fusion in
patients with hypereosinophilia across 8 published series enrolling
more than 10 patients was 23% (range 3%-56%).2 Larger studies con-
ducted in developing countries indicate that the FIP1L1-PDGFRA fusion

Am J Hematol. 2017;92:1243–1259. wileyonlinelibrary.com/journal/ajh V

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occurs in approximately 10% or less of patients with idiopathic
hypereosinophilia.3–5 Although usually diagnosed between the ages of
20 and 50, idiopathic hypereosinophilia or CEL may arise at the
extremes of age, with infrequent cases being described in infants and
6–8
children. In the SEER database of 131 incident cases between 2001
and 2005, the male-to-female ratio was 1.47, and rates increased with
age to a peak between 65 and 74 years.1 For reasons that are
unknown, the overwhelming majority of patients with FIP1L1-PDGFRA
3,9,10
or myeloproliferative variants of HES are male, whereas other
eosinophilia subtypes exhibit no clear gender bias.
1.2 | Definition of eosinophilia and classification
The upper limit of normal for the range of % eosinophils in the periph-
eral blood is 3%-5% with a corresponding absolute eosinophil count
(AEC) of 350–500/mm3.11,12 The severity of eosinophilia has been
arbitrarily divided into mild (AEC from the upper limit of normal to
1500/mm3), moderate (AEC 1500–5000/mm3) and severe (AEC
>5000/mm3).11–13
The classification of eosinophilic diseases was revised in the 2008
World Health Organization scheme of myeloid neoplasms and reaf-
firmed in 2016 (Table 1).14,15 In recognition of the growing list of recur-
rent, molecularly-defined primary eosinophilias resulting from fusion
tyrosine kinase genes, the major category “Myeloid/lymphoid neo-
plasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or
FGFR1 or with PCM1-JAK2” has been defined, with the latter fusion,
PCM1-JAK2, added as a provisional entity in 2016.15 Within the major
WHO category of myeloproliferative neoplasms (MPNs), “chronic
eosinophilic leukemia-not otherwise specified” (CEL-NOS) is one of
16
seven disease entities within this group (Table 1). CEL-NOS is
defined by absence of the Philadelphia chromosome or a rearrange-
ment involving PDGFRA/B and FGFR1, and the exclusion of other acute
or chronic primary marrow neoplasms associated with eosinophilia
such as acute myeloid leukemia (AML), myelodysplastic syndrome
(MDS), systemic mastocytosis (SM), the classic MPNs (chronic myeloid
leukemia, polycythemia vera, essential thrombocythemia, and primary
myelofibrosis), and MDS/MPN overlap disorders (e.g., chronic myelo-
monocytic leukemia, CMML) (Table 2). CEL-NOS is morphologically
characterized by an increase in blasts in the bone marrow or blood (but
fewer than 20% to exclude acute leukemia as a diagnosis), and/or there
is evidence for a clonal marker.16 A diagnosis of idiopathic HES
requires exclusion of all primary and secondary causes of hyerpeosino-
philia as well as lymphocyte-variant hypereosinophilia (Table 2). The
modern definition of HES is a vestige of the historical criteria outlined
by Chusid and colleagues in 1975: the absolute eosinophil count
is > 1500/mm for more than 6 months, and tissue damage is pres-
3
ent.17 The requirement that eosinophilia persist for more than 6
months is less consistently embraced today because of the availability
of more sophisticated tools to rapidly evaluate eosinophilia and the
need for some patients to receive expedited treatment to minimize
organ damage. In contrast to “HES,” “idiopathic hypereosinophilia” is
16
the preferred term when end-organ damage is absent. Because of
the increasing proportion of cases in which a clonal marker can be
GOTLIB ET AL.
identified, the pool of patients with classically defined idiopathic HES
has diminished. HES can be considered a provisional diagnosis until a
primary or secondary cause of eosinophilia is ascertained.
In 2011, the Working Conference on Eosinophil Disorders and Syn-
dromes proposed a new terminology for eosinophilic syndromes.18 The
panel recommended the higher-level term “Hypereosinophilia (HE)” for
persistent and marked eosinophilia (AEC > 1500/mm3). In turn, HE sub-
types were divided into a hereditary (familial) variant (HEFA), HE of unde-
termined significance (HEUS), primary (clonal/neoplastic) HE produced by
clonal/neoplastic eosinophils (HEN), and secondary (reactive) HE (HER).
HEUS was introduced as a novel term in lieu of “idiopathic hypereosino-
philia.” Any HE (not just idiopathic) associated with organ damage is
referred to as “HES” with specific variants designated by subscripts (e.g.,
HESUS, HESN, and HESR). Additional recommendations advanced by the
consensus panel are summarized in their report.
1.3 | Clinical presentation and diagnosis
The varied clinical presentations of primary eosinophilias/HES reflect
their heterogeneous pathophysiology. In two retrospective series pub-
lished in 1982 and 2009, eosinophilia was an incidental finding in 12%
and 6% of patients, respectively.19,20 The most common presenting
signs and symptoms were weakness and fatigue (26%), cough (24%),
dyspnea (16%), myalgias or angioedema (14%), rash or fever (12%), and
rhinitis (10%).21 In HES, leukocytosis (e.g., 20,000–30,000/mm3 or
higher) with peripheral eosinophilia in the range of 30%-70% is a com-
mon finding17,19–22; the aforementioned retrospective analysis of 188
patients from 2009 observed a mean peak eosinophil count of 6600/
mm3 with a range of 1500–400,000/mm3.20 Other hematologic find-
ings include peripheral blood or bone marrow neutrophilia, basophilia,
myeloid immaturity, and both mature and immature eosinophils with
varying degrees of dysplasia.22–24 In one series, anemia was present in
53% of patients, thrombocytopenia was more common than thrombo-
cytosis (31% vs. 16%), and bone marrow eosinophilia ranged from 7–
57% (mean 33%).24 Marrow findings of Charcot-Leyden crystals, and in
some cases, increased blasts and marrow fibrosis, are also observed.24
Essentially all organ systems may be susceptible to the effects of
sustained eosinophilia [reviewed in 25]. During follow-up of patients
with hypereosinophilia, dermatologic involvement was the most com-
mon clinical manifestation reported in 69% of patients, followed by
pulmonary (44%) and gastrointestinal (38%) manifestations. Cardiac
disease unrelated to hypertension, atherosclerosis or rheumatic disease
was eventually identified in 20% of patients (only 6% at the time of ini-
tial presentation).20 Progressive heart failure is a proto-typical example
of eosinophil-mediated organ injury. It involves a multi-step pathophys-
iological process involving eosinophil infiltration of cardiac tissue and
release of toxic mediators from eosinophils [reviewed in 19, 25]. Endo-
cardial damage with resulting platelet thrombus can lead to mural
thrombi and increased embolic risk. In the later fibrotic stage, fibrous
thickening of the endocardial lining can evolve to a restrictive cardio-
myopathy.19,25 Valvular insufficiency results from mural endocardial
thrombosis and fibrosis involving leaflets of the mitral or tricuspid
valves.26–28
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T AB LE 1 Revised 2016 World Health Organization (WHO) classification of myeloid neoplasms

1. Acute myeloid leukemia and related neoplasms

2. Myeloproliferative neoplasms (MPN)

· Chronic myeloid leukemia, BCR-ABL1 positive
· Chronic neutrophilic leukemia
· Polycythemia vera
· Primary myelofibrosis (PMF)
i PMF, prefibrotic/early stage
ii PMF, overt fibrotic stage
· Essential thrombocythemia
· Chronic eosinophilic leukemia, not otherwise specified
· Myeloproliferative neoplasms, unclassifiable

3. Myelodysplastic syndromes (MDS)

· MDS with single lineage dysplasia
· MDS with ring sideroblasts (MDS-RS)
·
MDS-RS with single lineage dysplasia
·
MDS-RS with multilineage dysplasia
· MDS with multilineage dysplasia
· MDS with excess blasts
· MDS with isolated del(5q)
· MDS, unclassifiable
i Provisional entity: Refractory cytopenia of childhood
· Myeloid neoplasms with germ line predisposition

4. MDS/MPN
· Chronic myelomonocytic leukemia
· Atypical chronic myeloid leukemia, BCR-ABL1 negative
· Juvenile myelomonocytic leukemia
· MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
· MDS/MPN, unclassifiable

5. Mastocytosis

6. Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2
· Myeloid/lymphoid neoplasms with PDGFRA rearrangement
· Myeloid neoplasms with PDGFRB rearrangement
· Myeloid/lymphoid neoplasms with FGFR1 abnormalities
· Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

2 | DIAGNOSIS lymphoma,33 and acute lymphoblastic leukemias.34 Rare conditions

associated with eosinophilia include familial eosinophilia whose genetic
2.1 | Step 1: Exclude secondary (reactive) causes of basis remains unknown, hyper IgE Syndrome, Omenn Syndrome, epi-
eosinophilia sodic angioedema and eosinophilia (Gleich’s syndrome), and
eosinophilia-myalgia syndrome (e.g., possibly related to tryptophan
Secondary eosinophilia has numerous causes that may require diagnos-
ingestion, or of historical interest, the epidemic of toxic-oil syn-
 of different sub-specialty consultants. In
tic evaluation by a cadre
drome).18 Repeated ova and parasite testing, stool culture, and anti-
developing countries, eosinophilia most commonly derives from infec-
body testing for specific parasites (e.g., strongyloides) is paramount for
tions, particularly tissue-invasive parasites.13 Allergy/atopy and hyper-
identifying infectious etiologies in the appropriate clinical context.
sensitivity conditions, drug reaction, collagen-vascular disease (e.g.,
Additional laboratory and imaging tests (e.g., chest-x-ray, electrocardio-
Churg-Strauss Syndrome, granulomatosis with polyangiitis [Wegener’s],
gram and echocardiography, CT scan of the chest, abdomen/pelvis) are
systemic lupus erythematosus), pulmonary eosinophilic diseases (e.g.,
guided by the patient’s travel history, presenting symptoms, and find-
idiopathic acute or chronic eosinophilia pneumonia, tropical pulmonary
ings on physical examination. For eosinophilic lung diseases, pulmonary
eosinophilia, allergic bronchopulmonary aspergillosis, etc), allergic gas-
function testing, bronchoscopy, serologic tests (e.g., aspergillus IgE to
troenteritis (with associated peripheral eosinophilia), and metabolic
evaluate for allergic bronchopulmonary aspergillosis [ABPA]) may be
conditions such as adrenal insufficiency are diagnostic considerations
obtained to further characterize lung involvement.
in the appropriate clinical context.29–31 Nonmyeloid malignancies may
be associated with secondary eosinophilia which results from the pro-
2.2 | Step 2: Evaluate for primary (clonal) eosinophilia
duction of cytokines such as IL-3, IL-5, and GM-CSF which promote
eosinophil differentiation and survival. For example, these cytokines If secondary causes of eosinophilia are excluded, the work-up should
32
may be elaborated from malignant cells in T-cell lymphomas, Hodgkin proceed to the evaluation of a primary bone marrow disorder.
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1246 GOTLIB ET AL.

T AB LE 2 Revised 2016 World Health Organization Classification of Eosinophilic Disorders41

Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2

Diagnostic criteria of an MPNa with eosinophilia associated with FIP1L1-PDGFRA

A myeloid or lymphoid neoplasm, usually with prominent eosinophilia

and

Presence of a FIP1L1-PDGFRA fusion gene or a variant fusion gene with rearrangement of PDGFRA-b

Diagnostic criteria for myeloid/lymphoid neoplasms associated with ETV6-PDGFRB fusion gene or other rearrangement of PDGFRBc

A myeloid or lymphoid neoplasm, often with prominent eosinophilia and sometimes with neutrophilia or monocytosis

and

Presence of t(8;12)(q31q33;p12) or a variant translocationd or demonstration of an ETV6-PDGFRB fusion gene or rearrangement of PDGFRB

Diagnostic criteria of MPN or acute leukemia associated with FGFR1 rearrangement

A myeloproliferative or myeiodysplastic/myeloproliferative neoplasm with prominent eosinophilia, and sometimes with neutrophilia or monocytosis

or

Acute myeloid leukemia or precursor T-cell or precursor B-cell lymphoblastic leukemia/lymphoma or mixed phenotype acute leukemia
(usually associated with peripheral blood or BM eosinophilia)

and

Presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts, or both

Diagnostic criteria for myeloid/lymphoid neoplasms with PCM1-JAK2

A myeloid or lymphoid neoplasm, often with prominent eosinophilia

and

Presence of t(8;9)(p22;p24.1) or a variant translocation leading to JAK2 rearrangemente

CEL, NOS

There is eosinophilia (eosinophil count >1.5 x 109/L)

Not meeting WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, PV, ET, PMF, CNL, CMML, or atypical CML

No rearrangement of PDGFRA, PDGFRB, or FGFR1; no PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion gene

The blast cell count in the peripheral blood and BM is less than 20%, and inv(16)(p13.1q22), t(16;16)(p13;q22) and other diagnostic features of AML
are absent

There is a clonal cytogenetic or molecular genetic abnormality, or blast cells are 2% in the peripheral blood or >5% in the BM

Idiopathic HES

Exclusion of the following:

Reactive eosinophilia

Lymphocyte-variant hypereosinophilia (cytokine-producing, immunophenotypically-aberrant T-cell population)

CEL, NOS

WHO-defined myeloid malignancies associated eosinophilia (eg, MDS, MPNs, MDS/MPNs, or AML)

Eosinophilia-associated MPNs or AML/ALL with rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2

The absolute eosinophil count of >1.5X109/L must persist for at least 6 mo, and tissue damage must be present. If there is no tissue
damage, idiopathic HES is the preferred diagnosis.
a
Patients presenting with myeloproliferative neoplasm, AML, or lymphoblastic leukemia/lymphoma with eosinophilia and a FIP1L1-PDGFRA fusion gene
are also assigned to this category.
b
lf appropriate molecular analysis is not available, this diagnosis should be suspected if there is a Ph-chromosome-negative MPN with the hematologic
features of chronic eosinophilic leukemia associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase, and
increased BM mast cells.
c
Cases with fusion genes typically associated only with BCR-ABL1-like B-lineage ALL are specifically excluded.
d
Because t(5;12)(q31q33;p12) does not always lead to an ETV6-PDGFRB fusion gene, molecular confirmation is highly desirable. If molecular analysis
is not available, this diagnosis should be suspected if there is a Ph-chromosome-negative MPN associated with eosinophilia and with a translocation
with a 5q3133 breakpoint.
e
Other variants giving rise to a fusion gene between JAK2 and an alternative partner include ETV6-JAK2 [t(9; 12)(p24.1;p13.2)] or BCR-JAK2 [t(9;22)
(p24.1;q11.2)].

GOTLIB ET AL.
Examination of the blood smear and blood tests (e.g., circulating blasts,
dysplastic cells, monocytosis, elevated serum B12 or tryptase level) in
conjunction with bone marrow morphologic, cytogenetic, and immuno-
phenoytpic analysis will help ascertain whether the differential diagno-
sis of eosinophilia includes a well-defined WHO myeloid neoplasm
such as systemic mastocytosis, chronic myeloid leukemia, acute mye-
loid leukemia (especially the historically-defined M2 and M4 Eo
French-American-British subtypes), myelodysplastic syndrome (MDS),
or MDS/MPN overlap disorder (e.g., CMML). Although not formally
included in the WHO monograph, the term “myeloproliferative variant
of hypereosinophilia” has been used to refer to some of these marrow-
derived eosinophilic myeloid malignancies because of clinicopathologic
similarity to CML and the BCR-ABL1-negative MPNs.9,25
Laboratory evaluation of primary eosinophilia should begin with
screening of the peripheral blood for the FIP1L1-PDGFRA gene fusion
(by RT-PCR or interphase/metaphase FISH) (Figure 1). FISH probes
that hybridize to the region between the FIP1L1 and PDGFRA genes
are used to detect the presence of the cytogenetically occult 800-kb
deletion on 4q12 that results in FIP1L1-PDGFRA. 9,35
Since the CHIC2
gene is located in this deleted genetic segment, this widely available
clinical test is referred to as “FISH for the CHIC2 deletion”. 35
In instan-
ces where FIP1L1-PDGFRA screening is not available, evaluation of the
serum tryptase can be a useful surrogate marker for FIP1L1-PDGFRA-
positive disease since increased levels segregate with this molecular
abnormality and myeloproliferative variants of hypereosinophilia.36
FIP1L1-PDGFRA has also been also identified in cases where bone mar-
rows show increased mast cell numbers with associated peripheral
4 gene rearrangement studies) which may be associated with excessive
eosinophilia. The bone marrows of such patients typically exhibit loose
mast cell clusters compared to classic SM with dense mast cell aggre-
gates associated with the KIT D816V mutation.4 In both disease sub-
types, mast cells stain for tryptase, CD117, and CD25, and the
37
marrows frequently exhibit increased fibrosis. The FIP1L1-PDGFRA
fusion has also been found in cases of AML and T-cell lymphoblastic
lymphoma associated with eosinophilia.38 In addition to dysregulation
of PDGFRA by fusion to FIP1L1 or other partner genes, activating point
mutations have been identified in PDGFRA in patients with hypereosi-
nophilia.39 Although there was variability in their transforming ability,
injection of cells harboring these mutants into mice induced a
leukemia-like disease. Imatinib treatment significantly decreased leuke-
mic growth and prolonged survival.39
Absence of the FIP1L1-PDGFRA fusion should prompt evaluation
for other primary eosinophilias associated with recurrent molecular
abnormalities. Molecular evidence for a PDGFRA, PDGFRB, or FGFR1
fusion gene is often accompanied by its abnormal karyotype equiva-
lent: rearrangement of 4q12 (PDGFRA fusion partners besides FIP1L1),
5q31–33 (PDGFRB) or 8p11–12 (FGFR1).14 Despite the rare frequency
(<1%) of PDGFRB-rearrangements in cytogenetically-defined cases of
CMML and other myeloid neoplasms (e.g., atypical CML, juvenile
myelomonocytic leukemia, MDS/MPN overlap disorders),40 their iden-
tification is critical given their responsiveness to imatinib. Over 30
41
gene fusion partners of PDGFRB have been described. Eosinophilic
myeloid neoplasms related to fusions involving the FGFR1 gene are
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1247
similarly rare.14 In these cases, the association of t(8p11–12) break-
point with lymphoblastic lymphoma with eosinophilia and myeloid
hyperplasia was first described in 1995, and was previously referred to
as “8p11 myeloproliferative syndrome” or “stem cell leukemia/lym-
phoma.” Following the discovery of the ZNF198-FGFR1 fusion gene in
1998 by several groups,42–45 some 14 fusion partners of FGFR1 have
been reported.41 The PCM1-JAK2 fusion was added to this WHO
major category as a provisional entity. Fusion tyrosine kinases involving
FLT3 (most commonly the ETV6-FLT3 fusion) typically present as an
MPN and/or T-cell acute lymphoblastic leukemia/lymphoma with
eosinophilia,46 but have not yet been formally added to this category.41
JAK2 and FLT3 rearrangements can be surmised by reciprocal translo-
cations involving the 9p24 and 13q12 breakpoints, respectively.
A negative screen for PDGFRA/B- or FGFR1-rearranged eosino-
philias should prompt consideration of a diagnosis of CEL-NOS when
there is cytogenetic and/or morphologic evidence of an eosinophilic
myeloid malignancy that is otherwise not classifiable.15 CEL- NOS may
be distinguished from HES by the presence of a nonspecific clonal
cytogenetic abnormality or increased blast cells (>2% in the peripheral
blood or > 5% in the bone marrow, but < 20% blasts in both compart-
ments). The marrow morphology of patients with CEL-NOS can be dis-
tinguished from patients with HES, and is correlated with a higher
frequency of abnormal karyotypes, myeloid mutations, and shortened
survival compared to the latter group.47
Lymphocyte-variant hypereosinophilia is a more obscure diagnos-
tic entity characterized by an abnormal T-cell population (demonstrated
by peripheral blood lymphocyte immunophenotyping or T cell receptor
eosinophilopoietic cytokine production in vitro (e.g., serum interleukin-
5).16,48,49 If none of the aforementioned conditions is identified, a diag-
nosis of HES is made if organ damage is present, and a diagnosis of idi-
opathic hypereosinophilia is rendered if organ compromise is not
found. With the availability of next-generation sequencing panels, iden-
tification of additional mutations in cases of idiopathic hypereosino-
philia/HES is expected to be more commonplace. For example, among
426 patients in the German Registry with hypereosinophilia of
unknown significance, KIT D816V and JAK2 V617F mutations were
identified in 3% and 4% of patients, respectively.50 Another study
found myeloid mutations in 14/51 patients with a diagnosis of HES,
including a single mutated gene in 7 patients and 2 or more mutated
genes in another 7 patients. The most commonly mutated genes were:
ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and
NOTCH1 (14%). Patients with HES ultimately found to have positive
sequencing results exhibited a prognosis that was inferior to HES
patients without mutation findings, but similar to patients with CEL-
NOS.51
2.3 | Lymphocyte-variant hypereosinophilia
Some patients may exhibit expansion of a cytokine-producing, immu-
nophenotypically-aberrant T-cell population.16,49 The condition is a
mixture of clonal and reactive processes: it is clonal with regard to the
production of abnormal T-cell lymphocytes; however, the eosinophilia
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1248 GOTLIB ET AL.

FIGURE 1 Diagnostic and Treatment Algorithm Based on Revised 2016 WHO Classification of Eosinophilic Disorders [Color figure can be
viewed at wileyonlinelibrary.com]

is reactive to the eosinophilopoietic growth factors elaborated by the T-
cells. The immunophenotype of these lymphocytes include double-
1 - -
negative, immature T-cells (e.g., CD3 CD4 CD8 ) or absence of CD3
(e.g., CD3-CD41), a normal component of the T-cell receptor
complex.52–54 Additional immunophenotypic abnormalities include
elevated CD5 expression on CD3-CD41 cells, and loss of surface CD7
and/or expression of CD27.49 These patients typically have cutaneous
signs and symptoms as the primary disease manifestation. However, a
recent series of 21 patients with a CD3-CD41 T-cell phenotype showed
that involvement of additional organ systems was prevalent, including

GOTLIB ET AL.
superficial adenopathy (62%), rheumatologic (29%), gastrointestinal
(24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). 55
In patients with T-cell mediated hypereosinophilia with elevated
IgE levels, lymphocyte production of IL-5, and in some cases IL-4 and
IL-13, suggests that these T-cells have a helper type 2 (Th2) cytokine
profile.49,52–54,56,57 In a study of 60 patients primarily from dermatol-
ogy clinics, 16 demonstrated circulating T-cells with an abnormal
48
immunophenotype. Clonal rearrangement of T-cell receptor genes
was demonstrated in half of these individuals (8/60 total patients). The
abnormal T-cells secreted high levels of interleukin-5 in vitro, and dis-
played an activated immunophenotype (e.g., CD25 and/or HLA-DR
expression). A case of lymphocyte-variant hypereosinophilia was
reported in a patient with chronic active Epstein-Barr virus infection
and an EBV-infected T-cell clone producing eosinophilopoietic cyto-
kines. Slightly elevated EBV DNA levels were detected in 2 of an addi-
tional 15 lymphocyte-variant hypereosinophilia patients tested, but the
causal relationship EBV and this subtype of eosinophilia is unclear.58
Consensus criteria for the diagnosis of lymphocyte-variant hyper-
eosinophilia have not been established. The finding of isolated T-cell
clonality by PCR without T-cell immunophenotypic abnormalities or
demonstration of Th2 cytokine production is not felt to be sufficient to
make a diagnosis of this eosinophilia variant.59 Despite a recent study
demonstrating that a high proportion of idiopathic HES patients exhibit
a clonal T-cell receptor gene rearrangement by PCR (18/42 patients,
43%), it is unclear whether such clonal T-cell populations are always
relevant to the disease process. 60
Detection of elevated serum levels
of TARC, a chemokine implicated in Th2-mediated diseases, in addition
to the finding of increased in vitro production of cytokines from cul-
tured peripheral blood mononuclear cells and/or T-cells (research-
based assays), may provide additional support for a diagnosis of
lymphocyte-variant hypereosinophilia. 20,59,61
3 | RISK STRATIFICATION
Older case series indicate that lives of patients with HES were over-
shadowed by early cardiac death. A review of 57 HES cases published
through 1973 reported a median survival of 9 months and the 3-year
survival was only 12%.17 Patients usually presented with advanced dis-
ease, with congestive heart failure accounting for 65% of deaths at
autopsy. In addition to cardiac disease, peripheral blood blasts or a
WBC count greater than 100,000/mm3 were poor prognostic factors.16
A later report of 40 HES patients cited a 5-year survival rate of 80%,
decreasing to 42% at 15 years.23 Factors predictive of a worse outcome
included the presence of a concurrent myeloproliferative syndrome,
corticosteroid-refractory hypereosinophilia, cardiac disease, male sex,
and the height of eosinophilia.23 A recent retrospective review of 247
HES patients at the Mayo Clinic identified 23 subjects who died during
the 19 years of the review period. The cause of death was identified in
15 (65%) patients, including the following etiologies: cardiac dysfunc-
tion (33%), infection (20%), unrelated malignancy (20%), thrombo-
62
embolic phenomena (13%), and vascular disease (13%). In a recent
Mayo Clinic report of 98 patients with HES and idiopathic
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1249
hypereosinophilia,63 a multivariate analysis revealed that age >60 years,
hemoglobin < 10 g/dL, cardiac involvement, and hepatosplenomegaly
were associated with inferior overall survival. Eleven patients (11%) har-
bored a pathogenetic mutation in one of the following genes: TET2,
ASXL1, KIT, IDH2, JAK2, SF3B1, and TP53, but the presence of one of
the mutations was only significant in a univariate analysis of survival.
The prognosis of WHO-defined CEL-NOS is poor. In a recently
reported cohort of 10 patients, the median survival was 22.2 months,
and 5 of the 10 patients developed acute transformation after median
of 20 months from diagnosis.64 Three of 5 patients who did not
develop AML died with active disease; one patient underwent an allo-
geneic stem-cell transplant and maintained a long-term remission, and
the remaining patient achieved a complete remission on imatinib and
hydroxyurea.64
In the lymphocyte-variant of hypereosinophilia, an indolent disease
course is usually observed. However, patients may infrequently
zary syndrome, indicating this
develop either T-cell lymphoma or Se
condition has malignant potential.49,55 Accumulation of cytogenetic
changes (e.g., partial 6q and 10p deletions, trisomy 7) in T-cells, and
proliferation of lymphocytes with the CD3-CD41 phenotype have
been observed with progression to lymphoma.57,65–67
In WHO-defined myeloid malignancies, the prognostic importance
of associated eosinophilia has been only been studied in few diseases.
In a series of 123 patients with systemic mastocytosis, eosinophilia
was prevalent in 34% of cases, but was prognostically neutral and not
affected by exclusion of FIP1L1-PDGFRA-positive cases.68 In a study of
1008 patients with de novo MDS, eosinophilia (and basophilia) pre-
dicted a significantly reduced survival without having a significant
impact on leukemia-free survival.69 A retrospective of 288 individuals
with newly diagnosed MDS revealed that significantly higher numbers
of patients with eosinophilia or basophilia (compared to patients with
neither) had chromosomal abnormalities carrying an intermediate or
poor prognosis.70 In addition, the overall survival rate was significantly
lower, and evolution to AML occurred more frequently.
4 | RISK-ADAPTED THERAPY
4.1 | General considerations
It is difficult to predict what duration and severity of eosinophilia will
precipitate tissue damage in individual patients. Inadequate data exists
to support initiation of therapy based on a specific eosinophil count in
the absence of organ disease, although an absolute eosinophil count of
1500–2000/mm3 has been recommended by some as a threshold for
starting treatment.71 Treatment algorithms have incorporated serial
monitoring of eosinophil counts, bone marrow aspiration and biopsy
with cytogenetics, evaluation of clonality (e.g., T-cell receptor gene
rearrangement, immunophenotyping), and directed organ assessment
(e,g. echocardiography, pulmonary function testing) in order to identify
occult organ disease and defined causes of eosinophilia which may
emerge after an initial diagnosis of HES.21,72
Given the historically poor-prognosis of chronic eosinophilic leuke-
mias and HES, and the exquisite sensitivity to imatinib in patients with
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rearranged PDGFRA/B, consensus has emerged that these individuals
be treated in the absence of organ dysfunction. Proactive treatment
has the potential to not only forestall tissue damage, but also to
achieve complete molecular remissions.
In patients with eosinophilia-related organ damage (e.g., heart,
lungs, gastrointestinal, central nervous system, skin), risk-adapted ther-
apy rests on the premise of identifying the specific WHO-defined
eosinophilic disorder and individualizing treatment accordingly. For
patients with an eosinophilia-associated WHO-defined myeloid malig-
nancy (e.g., AML, MDS, systemic mastocytosis, CML other MPNs, and
MDS/MPN), therapy is dictated by disease-specific algorithms and
guidelines. As a multikinase inhibitor, imatinib has not only demon-
strated remarkable benefit in CML, but is now definitive first line ther-
apy in patients with FIP1L1-PDGFRA-positive disease, and the rare
patients with alternate PDGFRA fusions or rearranged PDGFRB. The
discussion of treatment options below will focus on the experience
with imatinib in PDGFRA/B-rearranged neoplasms and separately the
therapeutic options available for patients with CEL, NOS, HES, and
lymphocyte-variant hypereosinophilia, which is based primarily on small
case series and retrospective studies. The use of other chemotherapeu-
tics for HES, and recent investigational approaches with antibodies, will
also be addressed.
4.2 | PDGFRA/B-rearranged neoplasms: The imatinib
experience
The success of imatinib in CML led to its empiric use in patients with
hypereosinophilia who exhibited signs suggestive of a myeloprolifera-
tive disorder. Several case reports and small case series of HES patients
were published in 2001–2002 highlighting rapid and complete hemato-
logic responses to imatinib 100–400 mg daily.73–75 FIP1L1-PDGFRa
was ultimately identified as the therapeutic target of imatinib. 9,76
The
identification of the clonal marker FIP1L1-PDGFRA in these cases
operationally re-defined them as a form of chronic eosinophilic leuke-
mia, and now comprise the WHO major category of “myeloid and
lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA,
PDGFRB, or FGFR1, or PCM1-JAK2.” 14
The hematologic benefit of imatinib in FIP1L1-PDGFRA-positive
myeloid neoplasms has been confirmed in numerous studies. Molecular
remissions were first reported by the NIH group by PCR testing of the
peripheral blood in 5 of 6 FIP1L1-PDGFRA-positive patients after 1–12
months of imatinib therapy. 77
Several reports have now described
rapid induction of molecular remission in imatinib-treated FIP1L1-
PDGFRA positive patients or with bone marrow transplantation.
Although 100 mg daily may be sufficient to achieve a molecular remis-
sion in some patients, others may require higher maintenance doses in
the range of 300–400 mg daily. Maintenance dosing of 100–200 mg
weekly may be sufficient to achieve a molecular remission in some
patients.78 In a French Eosinophil Network series, a complete hemato-
logic response (CHR) was achieved in all patients, and complete molec-
ular response (CMR) in 95% of patients (average starting imatinib dose,
165 mg/d). For 29 patients, imatinib was tapered to a maintenance
79
dose of 58 mg/day, permitting CHR and CMR to be sustained. The
GOTLIB ET AL.
optimal imatinib dose which sustains a molecular remission has not
been defined.
The natural history of imatinib-treated FIP1L1-PDGFRA-positive
myeloid neoplasms was evaluated in an Italian prospective cohort of
27 patients with a median follow-up period of 25 months (range 15–
60 months).10 Patients were dose escalated from an initial dose of
100 mg daily to a final dose of 400 mg daily. Complete hematologic
remission was achieved in all patients within 1 month, and all patients
became PCR negative for FIP1L1-PDGFRA after a median of 3 months
of treatment (range 1 to 10 months). Patients continuing imatinib
remained PCR-negative during a median follow-up period of 19
months (range 6–561 months). Another European study prospectively
assessed the natural history of molecular responses to imatinib doses
of 100–400 mg daily.3 Among 11 patients with high pretreatment tran-
script levels, all achieved a 3-log reduction in transcript levels by one
year of therapy, and 9 of 11 patients achieved a molecular remission.
In a long-term follow-up analysis of the Mayo cohort of 18 imatinib-
treated FIP1L1-PDGFRA-positive patients, 1 patient with accelerated
disease at presentation transformed to AML, but the median survival
of the entire cohort was not reached and the otherwise excellent clini-
cal outcomes corroborated the findings of other studies.80
Although in-depth and durable molecular responses occur with
imatinib, discontinuation of the drug can lead to relapse.3,10 In a dose
de-escalation trial of imatinib in 5 patients who had achieved a stable
hematologic and molecular remission at 300–400 mg daily for at least
one year, molecular relapse was observed in all patients after 2–5
months of either dose imatinib reduction or discontinuation.81 Molecu-
lar remissions could be re-established with re-induction of imatinib in
all cases at a dose range of 100–400 mg daily. Hematologic relapse
was noted only several weeks after discontinuation of imatinib in 4
patients in a Mayo series.5 In the French series, imatinib was stopped
in 11 patients; 6 of the patients subsequently relapsed, but 5 remained
in persistent complete hematologic or molecular remission (range, 9–
88 months).79 In two patients with undetectable FIP1L1-PDGFRA tran-
scripts by PCR for four years, no evidence of disease was detected for
more than two years after discontinuation of imatinib.82 In sum, these
data indicate that imatinib can effectively suppress, but not eliminate
the FIP1L1-PDGFRA clone in most patients, although some may experi-
ence prolonged molecular remissions after stoppage of imatinib.
Ongoing treatment is generally recommended similar to CML guide-
lines, and the role of imatinib discontinuation requires further evalua-
tion in the context of clinical trials.
In contrast to CML, very few cases of acquired imatinib resistance
have been reported with more than 10 years of experience in treating
FIP1L1-PDGFRA-positive disease.9,83–85 Most of the cases have involve
the T674I mutation within the ATP-binding domain of PDGFRa and
have occurred during the blast of disease. The T674I mutation is analo-
gous to the T315I BCR-ABL mutation in CMLthat confers resistance to
the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib.86 One
patient with the FIP1L1-PDGFRA T674I mutation in blast crisis
responded briefly to sorafenib, but was followed by rapid emergence
of a pan-resistant FIP1L1-PDGFRA D842V mutant.85 Despite in vitro
 A JH |
GOTLIB ET AL. 1251

nanomolar activity of sorafenib, midostaurin (PKC412), or nilotinib

against the T674I mutant,87–90 these drugs have limited clinical activ-
ity.91 Thus far, the only report of primary resistance to imatinib relates
to the tandem PDGFRA mutations, S601P and L629P, identified in a
FIP1L1-PDGFRA-positive patient in the chronic phase of the disease.92
Similar to recent in vitro findings with a F604S mutation within FIP1L1-
PDGFRA, the L629P mutation may induce drug resistance to imatinib
by increasing stability of the fusion oncoprotein rather than interfering
with drug binding.93
In patients with rearrangements of PDGFRB or PDGFRA variants
other than FIP1L1-PDGFRA, case reports and series indicate that imati-
nib, usually given at doses of 400 mg daily, can elicit durable hemato-
logic and cytogenetic remissions [reviewed in 2; 94]. Similar to FIP1L1-
PDGFRA, FISH can be used to assess response to imatinib in PDGFRB-
rearranged cases (Figure 2). Long-term follow-up (median 10.2 years)
of PDGFRB-rearranged patients treated with imatinib for a median
duration of 6.6 years showed a 96% response rate and a 10-year over-
all survival rate of 90%. None of the patients who achieved a complete
cytogenetic (n 5 13) or molecular (n 5 8) remission lost their response
or exhibited progression to blast crisis.95
In the blast phase of PDGFRA or PDGFRB-rearranged disease, ima-
tinib can still be effective. In a case series of 17 patients blast phase or
sarcoma, 15 patients treated with imatinib monotherapy, achieved
durable complete hematologic and molecular remissions. Only 2 (12%)
of 17 patients died after a median observation time of 65 months
(range, 7–106).96
The natural history of patients with myeloid/lymphoid disease
with rearranged FGFR1 follows an aggressive course usually terminat-
ing in AML in 1–2 years.14 Therefore, intensive chemotherapy with
regimens such as hyper-CVAD (directed to treatment of T- or B-cell
lymphoma), followed by early allogeneic transplantation, is recom- FIGURE 2 Interphase FISH results using a break-apart FISH probe
mended. The data for use of small molecule inhibitors for patients with for the PDGFRB gene region in a patient with MDS/MPN with
FGFR1-rearranged disease is sparse. The small molecule midostaurin eosinophilia and an abnormal karyotype, t(5;12)(q31–33;p13). (A)
Representative interphase nucleus demonstrating a typical abnor-
(PKC412) inhibited the constitutively activated ZNF198-FGFR1 fusion
mal signal pattern of a split red and green signal (corresponding to
in vitro, as well as in a patient who exhibited a hematologic (but not the PDGFRB gene disruption; see arrows) and one intact red/green
cytogenetic) response.97 Ponatinib has activity against the FGFR1 tyro- fusion signal (corresponding to the normal/intact PDGFRB allele).
sine kinase98,99 and was recently shown to be active in a patient with Eighty five percent of nuclei were abnormal. (B) After 3 months of
BCR-FGFR1-positive trilineage T/B/myeloid mixed phenotype acute treatment with imatinib and normalization of blood counts, a repre-
sentative interphase nucleus demonstrates a normal FISH signal
leukemia where it produced marked reduction of bulky lymphadenopa-
pattern with two intact Red/Green fusion signals, indicating two
thy unresponsive to induction chemotherapy.100 When re-introduced intact copies of the PDGFRB gene region. All cells demonstrated a
after allogeneic transplantation, it elicited a substantial reduction of normal FISH pattern. Courtesy of Dr. Rhett P. Ketterling, Mayo
molecular minimal residual disease. However, the German group found Clinic, Rochester
either no evidence for sustained hematologic or cytogenetic responses
or progressive disease with either ponatinib or intensive chemotherapy kinases, respectively. For example, two reports highlighted complete
in 7 FGFR1-rearranged patients. Four of these patients underwent allo- hematologic remissions and cytogenetic responses (1 compete and 1
geneic HSCT and were reported in CMR and alive after a median time major) in 2 patients with chronic eosinophilic leukemia with the PCM1-
of 19 months (range, 8–36 months) after diagnosis and 13 months JAK2 fusion [t(8;9)(p22;p24)] treated with the JAK1/JAK2 inhibitor rux-
(range, 4–29 months) after allogeneic HSCT.101 Selective and potent olitinib.102,103 Hematologic and cytognetic remissions, however, can be
inhibitors of FGFR1 are in development that may offer benefit for this variable JAK2-rearranged patients, with some lasting only 1–2 years,
patient group. and HSCT should be therefore considered for suitable candi-
The use of small molecule inhibitors (e.g., against JAK2 and FLT3) dates.104,105 Similarly, in FLT3-rearranged cases, hematologic and cyto-
should be entertained for patients with JAK2 and FLT3 fusion tyrosine genetic responses are observed with FLT3/multikinase inhibitors such
 |
A JH
1252
as sorafenib or sunitinib, but durability can be brief, necessitating con-
106,107
sideration of HSCT.
Imatinib’s safety profile in eosinophilic disorders parallels the drug’s
good tolerability in CML. A few cases of cardiogenic shock have been
reported in FIP1L1-PDGFRA-positive patients after initiation of imati-
108,109
nib. Currently, prophylactic use of steroids during the first 7–10
days of imatinib treatment is recommended for patients with known
cardiac disease and/or elevated serum troponin levels which may be
related to eosinophil-mediated heart damage or other cardiac co-
morbidities. 109
4.2.1 | Summary
Imatinib is considered definitive treatment for PDGFRA/B-re-arranged
neoplasms with eosinophilia. The FDA-recommended starting dose for
patients with the FIP1L1-PDGFRA rearrangement is 100 mg daily.
Cumulative data with long-term follow-up indicate that this dose is suf-
ficient to elicit complete and durable hematologic and complete molec-
ular remissions. For patients with myeloid neoplasms (usually MDS/
MPNs) with eosinophilia and rearranged PDGFRB, the recommended
dose is 400 mg daily which reflects the dose consistently used in sev-
eral case series with excellent outcomes.
4.3 | Treatment of HES and CEL, NOS:
Corticosteroids, hydroxyurea, and interferon-alpha
For patients with strictly defined HES (e.g., exclusion of all other possi-
ble causes of hypereosinophilia), corticosteroids (e.g., prednisone 1 mg/
kg) are the mainstay of therapy and are effective in producing rapid
reductions in the eosinophil count. However, therapy can be compli-
cated by side effects in those patients requiring long-term treatment to
suppress eosinophilia and organ damage. In a retrospective analysis,
141/188 (75%) HES patients received corticosteroids as initial mono-
therapy with 85% of these individuals achieving a complete or partial
response after one month of treatment.20 In this series, the median
maximal dose was 40 mg (5 - 625 mg), the median maintenance dose
was 10 mg daily (range 1–40 mg daily) and the duration of therapy
ranged from 2 months to 20 years. In another retrospective series, the
median starting dose of prednisone was 30 mg daily (range 5–85 mg),
and the maintenance dose ranged from 5 mg twice weekly to 60 mg
daily. Twenty-one of 33 patients (64%) exhibited a complete resolution
of eosinophilia, 5 patients (15%) achieved a 50% reduction, and 7
patients (21%) were resistant or intolerant to corticosteroids.110 With
symptom control and reduction of the eosinophil count to below
1500/mm3, corticosteroids can usually be tapered. Recrudescence of
symptoms, signs of organ damage, and/or significant increase of the
eosinophil count with a prednisone dose > 10 mg daily is an indication
for addition of other agents.
Hydroxyurea is an effective first-line agent for HES which may be
used in conjunction with corticosteroids or in steroid nonrespond-
ers.19,21,111 A typical starting dose is 500 - 1000 mg daily. Hydroxyurea
was used in 64/188 patients (34%) in the retrospective study; among
18 patients receiving hydroxuyrea as monotherapy, 13 patients (72%)
GOTLIB ET AL.
achieved a complete or partial response.19 When hydroxyurea was
combined with corticosteroids, the overall response rate was 69%.
Interferon-a (IFN-a) can produce hematologic and cytogenetic
remissions in HES and CEL patients refractory to other therapies
including prednisone and/or hydroxyurea,112–118 or can be used in con-
junction with corticosteroids as a steroid-sparing agent for individuals
requiring higher doses of prednisone. Some have advocated its use as
initial therapy for these disorders.98 In the retrospective study, 46/188
patients were treated with IFN-a (mostly in combination with glucocor-
ticoids) with response rates of 50% and 75% as monotherapy or com-
bination therapy, respectively.19 The optimal starting or maintenance
dose of IFN-a has not been well-defined, but the initial dose required
to control eosinophil counts often exceeds the doses needed to main-
tain a remission.119 Initiation of therapy at 1 million units by subcutane-
ous injection three times weekly (tiw) and gradual escalation of the
dose to 3–4 million units tiw or higher may be required to control
hypereosinophilia in some patients. Remissions have been associated
with improvement in clinical symptoms and organ disease, including
hepatosplenomegaly,113,117 cardiac and thromboembolic complica-
tions,93,95 mucosal ulcers,115 and skin involvement.118 Treatment of
four HES patients with PEG-IFN-a-2b among a larger cohort of BCR-
ABL1-negative MPN cohort resulted in 1 complete and 1 partial
response, but side effects required that the initial study dose be
reduced from 3 to 2 mcg/kg/week.120 A lower starting dose of 90
mcg/kg weekly (e.g., 1–1.5 mcg/kg weekly) is better tolerated based
on the experience of PEG-IFN-a-2a in PV and ET.121,122 Side effects of
short- and longer-acting formulations of IFN-a are usually dose-
dependent and include can include fatigue and flu-like symptoms,
transaminitis, cytopenias, depression, hypothyroidism, and peripheral
neuropathy. Unlike hydroxyurea which is a teratogen, interferon-alpha
is considered safe for use in pregnancy.
Hematologic benefit has been observed with second- and third-
line agents, including vincristine,123,124 cyclophosphamide,125 and eto-
poside.126,127 Responses to 2-chlorodeoxyadenosine alone128 or in
combination with cytarabine,129 and cyclosporin-A130,131 have also
been reported in HES, with a discontinuation rate of 82% with CSA in
one series due to poor tolerance.20
In selected cases, patients with CEL, NOS or HES may benefit
from imatinib, usually administered at higher doses (> 400 mg daily).132
However, hematologic responses in this group are more often partial,
short-lived, and may reflect drug-related myelosuppression.9,10 Rare
complete responses may represent diagnostically occult PDGFRA or
PDGFRB mutations or other unknown pathogenetic targets.133 Clinical
trials with novel agents should always be considered.
4.3.1 | Summary
Corticosteroids are potent anti-eosinophil agents with established effi-
cacy in HES and should be considered first-line treatment. Similar to
other MPNs, hydroxyurea can serve as effective palliative chemother-
apy to control leukocytosis and eosinophilia, but with no proven role in
favorably altering the natural history of HES or CEL, NOS. Based on a
limited published literature, IFN-a has demonstrated hematologic
responses and reversion of organ injury in patients with HES and CEL.

GOTLIB ET AL.
The logic of using IFN-a in CEL is partly extrapolated from its efficacy
in other MPNs such as CML, as well as PV and ET, and evidence for
cytogenetic remitting activity. Although typically used as a second line-
agent in HES steroid-failures, IFN-a could be used as initial therapy in
patients with contra-indications or intolerance to steroid therapy. The
optimal dose and duration of IFN-a therapy in HES is unknown and is
tailored to individual response and tolerability.
4.4 | Treatment of lymphocyte-variant
hypereosinophilia
Patients with clonal population(s) of T-cells with an aberrant immuno-
phenotype and/or cytokine production should initially be treated with
corticosteroids. Patients who are refractory to therapy or exhibit
relapse may be considered for treatment with IFN-a or steroid-sparing
immunosuppressive agents. Among 16 lymphocyte-variant hypereosi-
nophilia patients with the aberrant CD3-CD41 immunophenotype, all
responded to corticosteroids, but 16 ultimately required steroid-
55
sparing agents. Hydroxyurea and imatinib are less likely to demon-
strate efficacy in this lymphocyte-variant of hypereosinophilia com-
pared to myeloproliferative forms of the disease which can be very
responsive to these drugs as discussed above. Elevated serum IgE and
TARC levels were associated with responsiveness to steroids in the
lymphocyte-variant of hypereosinophilia.20
4.4.1 | Summary
Corticosteroids are first-line therapy in patients with hypereosinophilia
in whom a clonal population of T-cells with an abnormal immunophe-
notype are identified and other causes of an elevated eosinophil count
are excluded.
4.5 | Antibody approaches for HES
4.5.1 | Mepolizumab
Anti-IL-5 antibody approaches have been studied in HES based on the
cytokine’s role as a differentiation, activation, and survival factor for
eosinophils. Mepolizumab is a fully humanized monoclonal IgG anti-
body that inhibits binding of IL-5 to the a chain of the IL-5 receptor
expressed on eosinophils.134 In HES patients, regression of constitu-
tional symptoms, eosinophilic dermatologic lesions, and improvements
FEV1 measurements in individuals with pulmonary disease have been
observed with anti-IL-5 antibody therapy.135–137 Among the few
patients studied, responses have not been predicted by pretreatment
serum IL-5 levels or presence of FIP1L1-PDGFRA. Rebound eosino-
philia, accompanied by increases in serum IL-5 levels, has been noted
in some cases, and tachyphylaxis has been observed with repeated
doses without development of neutralizing antibodies.137 In the largest
study of HES patients to date, the safety and steroid-sparing effects of
mepolizumab was evaluated in a randomized, double-blind, placebo-
138
controlled trial of 85 FIP1L1-PDGFRA-negative patients. Blood
eosinophil levels were stabilized at <1000 cells/mm3 on 20–60 mg/
day prednisone during a run-in period of up to 6 weeks. Patients were
subsequently randomized to intravenous mepolizumab 750 mg or
A JH |
1253
placebo every 4 weeks for 36 weeks. No adverse events were signifi-
cantly more frequent with mepolizumab compared to placebo. A signif-
icantly higher proportion of mepolizumab-treated HES patients versus
placebo were able to achieve the primary efficacy endpoint of a daily
prednisone dose of 10 mg daily for at least 8 consecutive weeks. In a
long-term follow of 78 patients treated for a mean exposure of 251
weeks (range 4–302 weeks), the median daily prednisone dose
decreased from 20 to 0 mg in the first 24 weeks, and 62% percent of
patients were prednisone-free without other HES medications for  12
consecutive weeks.139 Mepolizumab is not currently approved by the
FDA for HES (approved only for severe eosinophilic asthma), but is cur-
rently available on a compassionate use basis (clinicalTrials.gov Identi-
fier NCT00244686) for individuals with life-threatening HES who have
failed prior therapies.
Reslizumab is a humanized anti-IL5 IgG4 mAb currently in clinical
trials for pediatric subjects with eosinophilic esophagitis and for
patients with eosinophilic asthma, but has not yet been evaluated
extensively in HES.140 In a double-blind, placebo-controlled, random-
ized trial, reslizumab significantly reduced intraepithelial esophageal
eosinophil counts in children and adolescents with eosinophilic esopha-
gitis, but symptom improvement was observed in both treatment
groups.141 Benralizumab is an anti-IL5 receptor antibody that has been
shown to reduce the annual asthma exacerbation rate in two phase III
trials of patients with severe, uncontrolled eosinophilic asthma142,143
and is currently under evaluation for patients with HES (clinicaltrials.
gov identifier: NCT02130882).
It is unknown whether mepolizumab or other anti-IL5 antibody
approaches have a role in WHO-defined eosinophilic myeloid disor-
ders. However, preclinical models suggest a pathobiologic rationale for
their use. Mice expressing FIP1L1-PDGFRA in their bone marrow cells
only develop a general myeloproliferative disease.87 In contrast,
expression of FIP1L1-PDGFRA together with overexpression of IL-5
mimics eosinophilic disease much better in mice with typical features
of HES such as tissue infiltration of eosinophils.144
4.5.2 | Alemtuzumab
Alemtuzumab is an anti-CD52 monoclonal antibody that has been eval-
uated in idiopathic HES based on expression of the CD52 antigen on
eosinophils.145,146 Similar to mepolizumab, it has not been formally
evaluated in myeloid-related eosinophilias. In patients with refractory
HES, alemtuzumab administered intravenously at a dose of 5–30 mg
once to thrice weekly, elicited a complete hematologic remission (CHR)
in 10/12 subjects (83%), with 2 patients achieving a partial remis-
sion.147 Patients with CHR who received maintenance alemtuzumab
therapy exhibited significantly longer time to progression than patients
who were only observed. Eleven patients relapsed (only one while on
maintenance), and 6 were re-challenged with alemtuzumab. Five (83%)
achieved second CHR after a median of 3.5 weeks, for a median dura-
tion of 123 weeks.148
4.5.3 | Summary
Use of anti-IL-5 and anti-CD52 antibody approaches in the treatment
of HES remain investigational. Potential benefits include resolution of
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1254
eosinophilia and disease-related symptomology, and a steroid-sparing
effect (mepolizumab). However, with discontinuation of therapy, bene-
fits appear to be short-lived and the potential for rebound eosinophilia
exists. Maintenance therapy with these antibodies is generally required
to sustain responses.
5 | TRANSPLANTATION
Bone marrow/peripheral blood stem cell allogeneic transplantation has
been attempted in patients with aggressive disease. Disease-free sur-
vival ranging from 8 months to 5 years has been reported 149–154
with
154
one patient relapsing at 40 months. Allogeneic transplantation using
nonmyeloablative conditioning regimens have been reported in three
patients, with remission duration of 3–12 months at the time of last
reported follow-up.155,156 In one patient who underwent an allogeneic
stem cell transplantation from an HLA-matched sibling, the patient was
disease free at 3 years, and there was no evidence of the FIP1L1-
PDGFRA fusion which was present at diagnosis.157 Despite success in
selected cases, the role of transplantation in HES is not well
established.
6 | SUPPORTIVE CARE AND SURGERY
Leukapheresis can elicit transient reductions in high leukocyte and
eosinophil counts, but is not an effective maintenance therapy.158–160
Splenectomy has been performed for hypersplenism-related abdominal
pain and splenic infarction, but is not considered standard treat-
ment.22,161 Anticoagulants and anti-platelet agents have demonstrated
variable success in preventing recurrent thromboembolism.22,162,163
Advanced cardiac disease is less common today in patients with
eosinophilic disease. Cardiac surgery can extend the life of patients
with late-stage heart disease manifested by endomyocardial fibrosis,
mural thrombosis, and valvular insufficiency,19,21 Mitral and/or tricus-
pid valve repair or replacement164–168 and endomyocardectomy for
late-stage fibrotic heart disease165,169 can improve cardiac function.
Bioprosthetic devices are generally preferred over their mechanical
counterparts because of the reduced frequency of valve thrombosis.
7 | CONCLUDING REMARKS
A more sophisticated understanding of the cellular and molecular basis
of eosinophilic disorders has translated into more biologically-oriented
classification schemes which carry therapeutic implications. In this
regard, imatinib for has dramatically reversed the poor-prognosis of
patients previously diagnosed as “HES” and who likely represented a
significant portion of older series of patients who exhibited a poor
prognosis. Corticosteroids, interferon-alpha, hydroxyurea/other chem-
otherapy, and targeted antibodies can elicit clinical benefit in the pri-
mary eosinophilias, but response durability is variable, and treatment is
often complicated by both short- and long-term side effects. Regarding
future directions, the recently approved JAK1/2 inhibitor ruxolitinib
(and other JAK inhibitors currently being evaluated in phase I-III trials
GOTLIB ET AL.
of myelofibrosis) may have a role in patients with eosinophilic disease.
For example, rare patients with hypereosinophilia have been found to
carry the JAK2 V617F activating mutation.50,170,171 More germane to
eosinophil biology is the finding that the JAK2 pathway mediates anti-
apoptosis signals in eosinophils in response to GM-CSF and IL-5,172,173
in addition to FIP1L1-PDGFRa.174 Inhibition of this signaling cascade
may be a useful therapeutic approach across eosinophilic disorders
regardless of their subtype. In addition, the finding that PDGF receptor
fusion oncogenes skew proliferation and differentiation toward the
eosinophil lineage in a process that requires NF-jB suggests the possi-
bility for new treatments that target this pathway.175
C ONFLICT OF INT E RE ST S
Dr. Gotlib receives honoraria, serves on an advisory board, and
receives funding from Incyte, Inc. for administration of clinical trials.
R EF ER E NCE S
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How to cite this article: Gotlib J. World Health Organization-
defined eosinophilic disorders: 2017 update on diagnosis, risk
stratification, and management. Am J Hematol. 2017;92:1243–
1259. https://doi.org/10.1002/ajh.24880