ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

A JH

CME Information: World Health Organization-defined

eosinophilic disorders: 2014 update on diagnosis, risk
stratification, and management
Author: Jason Gotlib, M.D., M.S.
CME Editor: Ayalew Tefferi, M.D.

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䊏 Educational Objectives
Upon completion of this educational activity, participants will be better able to:

1. Understand the 2008 World Health Organization semi-molecular classification of eosinophilic disorders
2. Understand the algorithm for the diagnosis of eosinophilic conditions and treatment options based on disease subtype.

䊏 Activity Disclosures
No commercial support has been accepted related to the development or publication of this activity.

Author: Jason Gotlib, M.D., M.S. discloses honoraria for advisory board services and funding for clinical trials from Incyte, Inc.
CME Editor: Ayalew Tefferi, M.D. has no conflicts of interest to disclose.

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doi:10.1002/ajh.00032 American Journal of Hematology, Vol. 89, No. 3, March 2014 325
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material A JH
World Health Organization-defined eosinophilic disorders:
2014 update on diagnosis, risk stratification, and
management

Jason Gotlib*

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 (HE) has generally been defined as a peripheral blood eosinophil count
greater than 1,500/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 hybridization, 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 evaluation of
secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular
classification scheme of disease subtypes including “myeloid and lymphoid neoplasms with eosinophilia and
abnormalities of PDGFRA, PDGFRB, or FGFR1’, chronic eosinophilic leukemia, not otherwise specified” (CEL,
NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which 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., <1,500/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 diseases to imatinib. Corticosteroids
are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha
have demonstrated efficacy as initial 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 number of patients. Although
clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies,
their therapeutic role in primary eosinophilic diseases and HES has yet to be established.
Am. J. Hematol. 89:326–337, 2014. V C 2014 Wiley Periodicals, Inc.

䊏 Disease Overview
Epidemiology
The incidence and prevalence of hypereosinophilic syndrome (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 approximately 0.036 per 100,000 [1]. The incidence of eosi-
nophilias with recurrent genetic abnormalities (PDGFRA/B, FGFR1) comprises a minority of these patients. The median frequency of the FIP1L1-
PDGFRA fusion in patients with hypereosinophilia (HE) across eight published series enrolling more than 10 patients was 23% (range 3–56%) [2].
Larger studies conducted in developing countries indicate that the FIP1L1-PDGFRA fusion occurs in approximately 10–20% of patients with idio-
pathic HE [3–5]. Although usually diagnosed between the ages of 20 and 50, idiopathic HE or chronic eosinophilic leukemia (CEL) may arise at
the extremes of age, with infrequent cases being described in infants and children [6–8]. 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,

Division of Hematology, Stanford Cancer Center, Stanford, California

Conflict of interest: Dr. Gotlib receives honoraria, serves on an advisory board, and receives funding from Incyte, for administration of clinical trials
I cited Incyte because I included two references with the use of ruxolitinib for PCM1-JAK2 rearranged disease with eosinophilia
*Correspondence to: Jason Gotlib, Division of Hematology, Stanford Cancer Center, 875 Blake Wilbur Drive, Room 2324, Stanford, CA 94305-5821. E-mail:
jason.gotlib@stanford.edu
Received for publication: 17 December 2013; Accepted: 3 January 2014
Am. J. Hematol. 89:326–337, 2014.
Published online: 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.23664

C 2014 Wiley Periodicals, Inc.

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326 American Journal of Hematology, Vol. 89, No. 3, March 2014 doi:10.1002/ajh.23664
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
the overwhelming majority of patients with FIP1L1-PDGFRA or mye-
loproliferative variants of HES are male [3,9,10], whereas other eosin-
ophilia subtypes exhibit no clear gender bias.
Definition of eosinophilia and classification
The upper limit of normal for the range of % eosinophils in the
peripheral 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 1,500/mm3), moderate (AEC 1,500–5,000/mm3), and severe
(AEC > 5,000/mm3) [11–13].
The classification of eosinophilic diseases was revised in the 2008
World Health Organization scheme of myeloid neoplasms (Table I).
In recognition of the growing list of recurrent, molecularly defined
primary eosinophilias, a new major category was created, “Myeloid
and lymphoid neoplasms with eosinophilia and abnormalities of
platelet-derived growth factor receptor alpha (PDGFRA), platelet-
derived growth factor receptor beta (PDGFRB), or fibroblast growth
factor receptor 1 (FGFR1)” (Table I) [14]. Within the major WHO
category of myeloproliferative neoplasms (MPNs), “chronic eosino-
philic leukemia-not otherwise specified” (CEL-NOS) is one of eight
disease entities within this group (Table I) [15]. CEL-NOS is opera-
tionally defined by absence of the Philadelphia chromosome or a
rearrangement 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
TABLE I. 2008 World Health Organization (WHO) Classification of Myeloid
Malignancies
1. Acute myeloid leukemia and related disorders
2. Myeloproliferative neoplasms (MPN)
 Chronic myelogenous leukemia, BCR-ABL1 positive
 Chronic neutrophilic leukemia
 Polycythemia vera
 Primary myelofibrosis
 Essential thrombocythemia
 Chronic eosinophilic leukemia, not otherwise specified
 Mastocytosis
 Myeloproliferative neoplasms, unclassifiable
3. Myelodysplastic syndromes (MDS)
 Refractory cytopenia with uni-lineage dysplasia
䊏 Refractory anemia
䊏 Refractory neutropenia
䊏 Refractory thrombocytopenia
 Refractory anemia with ring sideroblasts
 Refractory cytopenia with multilineage dysplasia
 Refractory anemia with excess blasts (RAEB)
䊏 RAEB-1
䊏 RAEB-2
 Myelodysplastic syndrome with isolated del(5q)
 Myelodysplastic syndrome, unclassifiable
4. MDS/MPN
Chronic myelomonocytic leukemia
䊏 CMML-1
䊏 CMML-2
Atypical chronic myeloid leukemia, BCR-ABL1 negative
Juvenile myelomonocytic leukemia
MDS/MPN, unclassifiable
䊏 Refractory anemia with ring sideroblasts and
thrombocytosis (RARS-T)
5. Myeloid and lymphoid neoplasms associated with eosinophilia and
abnormalities of PDGFRA, PDGFRB, or FGFR1
Myeloid and lymphoid neoplasms associated with PDGFRA
rearrangement
Myeloid neoplasms associated with PDGFRB rearrangement
Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities.
doi:10.1002/ajh.23664
syndrome (MDS), systemic mastocytosis (SM), classic MPNs (chronic
myeloid leukemia, polycythemia vera, essential thrombocythemia, and
primary myelofibrosis), and MDS/MPN overlap disorders (e.g.,
chronic myelomonocytic leukemia, CMML; Table II). CEL-NOS is
histologically characterized by an increase in blasts in the bone mar-
row or blood (but fewer than 20% to exclude acute leukemia as a
diagnosis), and/or there is an evidence for clonality in the eosinophil
lineage [15]. A diagnosis of idiopathic HES requires exclusion of all
primary and secondary causes of hypereosinophilia as well as
lymphocyte-variant HE (Table II). The modern definition of HES
remains a vestige of the historical criteria outlined by Chusid et al. in
1975: the AEC is >1,500/mm3 for more than 6 months, and tissue
damage is present [16]. 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 eosino-
philia and the need for some patients to receive expedited treatment
to minimize organ damage. In contrast to “HES,” “idiopathic HE” is
the preferred term when end-organ damage is absent [15]. The pool
of classically defined idiopathic HES patients has diminished due to
an increasing proportion of cases which have been reassigned as clo-
nal marrow disorders. HES may therefore be considered a provisional
diagnosis until a primary or secondary cause of eosinophilia is
recognized.
In 2011, the Working Conference on Eosinophil Disorders and
Syndromes proposed a new terminology for eosinophilic syndromes
[17]. The panel recommended the higher level term “HE” for persis-
tent and marked eosinophilia (AEC > 1,500/mm3). In turn, HE sub-
types were divided into a hereditary (familial) variant (HEFA), HE of
undetermined 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 HE.” 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 recommenda-
tions advanced by the consensus panel are summarized in their
report.
Clinical presentation and diagnosis
The varied clinical presentations of primary eosinophilias/HES
reflect their heterogeneous pathophysiology. In two retrospective
series published in 1982 and 2009, eosinophilia was an incidental
finding in 12 and 6% of patients, respectively [18,19]. The most com-
mon presenting signs and symptoms were weakness and fatigue
(26%), cough (24%), dyspnea (16%), myalgias or angioedema (14%),
rash or fever (12%), and rhinitis (10%) [17]. In HES, leukocytosis
(e.g., 20,000–30,000/mm3 or higher) with peripheral eosinophilia in
the range of 30–70% is a common finding [16,18–20]; the aforemen-
tioned retrospective analysis of 188 patients from 2009 observed a
mean peak eosinophil count of 6,600/mm3 with a range of 1,500–
400,000/mm3 [18]. Other hematologic findings include peripheral
blood or bone marrow neutrophilia, basophilia, myeloid immaturity,
and both mature and immature eosinophils with varying degrees of
dysplasia [20–22]. In one series, anemia was present in 53% of patients,
thrombocytopenia was more common than thrombocytosis (31% vs.
16%), and bone marrow eosinophilia ranged from 7 to 57% (mean
33%) [22]. Marrow findings of Charcot–Leyden crystals, and some-
times increased blasts and marrow fibrosis, are also observed [22].
Essentially all organ systems may be susceptible to the effects of
sustained eosinophilia [reviewed in 23]. During follow-up of patients
with HE, dermatologic involvement was also the most common clini-
cal manifestation reported in 69% of patients, followed by pulmonary
(44%) and gastrointestinal (38%) manifestations. Cardiac disease
American Journal of Hematology, Vol. 89, No. 3, March 2014 327
Gotlib ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

TABLE II. 2008 World Health Organization Classification of Eosinophilic Disorders

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
Diagnostic criteria of an MPNa with eosinophilia associated with FIP1L1-PDGFRA
A myeloproliferative neoplasm with prominent eosinophilia
AND
Presence of a FIP1L1-PDGFRA fusion geneb
Diagnostic criteria of MPN associated with ETV6-PDGFRB fusion gene or other rearrangement of PDGFRB
A myeloproliferative neoplasm, often with prominent eosinophilia and sometimes with neutrophilia or monocytosis
AND
Presence of t(5;12)(q31q33;p12) or a variant translocationc 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 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 (usually associated with peripheral blood or bone
marrow eosinophilia)
AND
Presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts, or both
Chronic Eosinophilic Leukemia, Not Otherwise Specified (NOS)
1. There is eosinophilia (eosinophil count >1.5 3 109/L)
2. There is no Ph chromosome or BCR-ABL fusion gene or other myeloproliferative neoplasms (PV, ET, PMF, systemic mastocytosis) or MDS/MPN (CMML or
atypical CML)
3. There is no t(5;12)(q31q35;p13) or other rearrangement of PDGFRB
4. There is no FIP1L1-PDGFRA fusion gene or other rearrangement of PDGFRA
5. There is no rearrangement of FGFR1
6. The blast cell count in the peripheral blood and bone marrow is less than 20% and there is no inv(16)(p13q22) or t(16;16)(p13;q22) or other feature
diagnostic of AML
7. There is a clonal cytogenetic or molecular genetic abnormality, or blast cells are more than 2% in the peripheral blood or more than 5% in the bone
marrow.
Idiopathic Hypereosinophilic Syndrome (HES)
Exclusion of the following:
1. Reactive eosinophilia
2. Lymphocyte-variant hypereosinophilia (cytokine-producing, immunophenotypically aberrant T-cell population)
3. Chronic eosinophilic leukemia, NOS
4. WHO-defined myeloid malignancies associated eosinophilia (e.g., MDS, MPNs, MDS/MPNs, or AML)
5. Eosinophilia-associated MPNs or AML/ALL with rearrangements of PDGFRA, PDGFRB, or FGR1.
6. The absolute eosinophil count of >1,500/mm3 must persist for at least 6 months and tissue damage must be present. If there is no tissue damage,
idiopathic hypereosinophilia is the preferred diagnosis.

a
Patients presenting with acute myeloid leukemia or lymphoblastic leukemia/lymphoma with eosinophilia and a FIP1L1-PDGFRA fusion gene are also
assigned to this category
b
If appropriate molecular analysis is not available, this diagnosis should be suspected if there is a Ph-negative MPN with the hematological features of
chronic eosinophilic leukemia associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase and increased bone mar-
row mast cells.
c
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-negative MPN associated with eosinophilia and with a translocation with a 5q31–33 breakpoint.

unrelated to hypertension, atherosclerosis, or rheumatic disease was
eventually identified in 20% of patients (only 6% at the time of initial
presentation) [19]. Progressive heart failure is a proto-typical example
of eosinophil-mediated organ injury. It involves a multistep patho-
physiological process involving eosinophil infiltration of cardiac tissue
and release of toxic mediators from eosinophils [reviewed in 18,24].
Endocardial 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
cardiomyopathy [18,24]. Valvular insufficiency results from mural
endocardial thrombosis and fibrosis involving leaflets of the mitral or
tricuspid valves [25–27].
䊏 Diagnosis
Step 1: Exclude secondary (reactive) causes of
eosinophilia
Secondary eosinophilia has numerous causes which may require
diagnostic evaluation by a cadre of different subspecialty consultants.
In developing countries, eosinophilia most commonly derives from
infections, particularly tissue-invasive parasites [13]. Allergy/atopy and
hypersensitivity conditions, drug reaction, collagen-vascular disease
[e.g., Churg–Strauss Syndrome, granulomatosis with polyangiitis
(Wegener’s), systemic lupus erythematosus], pulmonary eosinophilic
diseases (e.g., idiopathic acute or chronic eosinophilia pneumonia, trop-
ical pulmonary eosinophilia, allergic bronchopulmonary aspergillosis,
etc.), allergic gastroenteritis (with associated peripheral eosinophilia),
and metabolic conditions such as adrenal insufficiency are diagnostic
considerations in the appropriate clinical context [28–30]. Nonmyeloid
malignancies may be associated with secondary eosinophilia which
results from the production of cytokines such as IL-3, IL-5, and GM-
CSF which promote eosinophil differentiation and survival. For exam-
ple, these cytokines may be elaborated from malignant cells in T-cell
lymphomas [31], Hodgkin’s disease [32], and acute lymphoblastic leu-
kemias [33]. Rare conditions associated with eosinophilia include fami-
lial eosinophilia whose genetic basis remains unknown, hyper IgE
Syndrome, Omenn Syndrome, episodic angioedema and eosinophilia
(Gleich’s syndrome), and eosinophilia-myalgia syndrome (e.g., possibly
related to tryptophan ingestion, or of historical interest, the epidemic of
toxic-oil syndrome) [17]. Repeated ova and parasite testing, stool cul-
ture, and antibody testing for specific parasites (e.g., Strongyloides) is
paramount for identifying infectious etiologies in the appropriate clini-
cal context. Additional laboratory and imaging tests (e.g., chest-x-ray,
electrocardiogram and echocardiography, CT scan of the chest, abdo-
men/pelvis) are guided by the patient’s travel history, presenting

328 American Journal of Hematology, Vol. 89, No. 3, March 2014 doi:10.1002/ajh.23664
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
Figure 1. Diagnostic and treatment algorithm based on 2008 WHO classification of eosinophilic disorders.
symptoms, and findings on physical examination. For eosinophilic lung
diseases, pulmonary function testing, bronchoscopy, serologic tests [e.g.,
aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis
(ABPA)] may be obtained to further characterize lung involvement.
Step 2: Evaluate for primary (clonal) eosinophilia
If secondary causes of eosinophilia are excluded, the work-up
should proceed to the evaluation of a primary bone marrow disorder.
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 immunophenoytpic analysis will help ascertain whether the dif-
ferential diagnosis of eosinophilia includes a well-defined WHO mye-
doi:10.1002/ajh.23664
loid neoplasm such as SM, chronic myelogenous leukemia, acute
myelogenous leukemia (especially the historically defined M2 and M4
Eo French-American-British subtypes), MDS, or MDS/MPN overlap
disorder (e.g., CMML). Although not formally included in the WHO
monograph, the term “myeloproliferative variant of HE” has been
used to refer to some of these marrow-derived eosinophilic myeloid
malignancies because of clinicopathologic similarity to CML and the
BCR-ABL-negative MPNs [9,23].
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; Fig. 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 [9,34]. As
American Journal of Hematology, Vol. 89, No. 3, March 2014 329
Gotlib
the CHIC2 gene is located in this deleted genetic segment, this widely
available clinical test is referred to as “FISH for the CHIC2 deletion”
[34]. In instances where FIP1L1-PDGFRA screening is not available,
evaluation of the serum tryptase can be a useful surrogate marker for
FIP1L1-PDGFRA-positive disease as increased levels segregate with
this molecular abnormality and myeloproliferative variants of HE
[35]. FIP1L1-PDGFRA has also been identified histopathologically
defined cases of SM with associated eosinophilia [4]. The bone mar-
rows of such patients typically exhibit less dense clusters of mast cells
by tryptase immunostaining are observed in SM with the highly prev-
alent KIT D816V mutation [4]. The FIP1L1-PDGFRA fusion has also
been found in cases of AML and T-cell lymphoblastic lymphoma
associated with eosinophilia [36]. 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 HE [37].
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 leukemic growth
and prolonged survival [37].
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
equivalent: rearrangement of 4q12 (PDGFRA fusion partners besides
FIP1L1), 5q31-33 (PDGFRB), or 8p11-13 (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 disor-
ders), their identification is critical given their responsiveness to ima-
tinib [38]. Over 20 gene fusion partners of PDGFRB have been
described. Eosinophilic myeloid neoplasms related to fusions involv-
ing the FGFR1 gene are similarly rare [14]. In these cases, the associa-
tion of t(8p11-13) breakpoint 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/lymphoma.” Following the discovery of the
ZNF198-FGFR1 fusion gene in 1998 by several groups [39–42], more
than 10 fusion partners of FGFR1 have been reported [reviewed in 2].
A negative screen for PDGFRA/B- or FGFR1-rearranged eosino-
philias should lend consideration to a diagnosis of CEL-NOS when
there is cytogenetic and/or morphologic evidence of a eosinophilic
myeloid malignancy that is otherwise not classifiable [15]. CEL-NOS
may be distinguished from HES by the presence of a nonspecific clo-
nal cytogenetic abnormality or increased blast cells (>2% in the
peripheral blood or >5% in the bone marrow, but <20% blasts in
both compartments). Lymphocyte-variant HE is a more obscure diag-
nostic entity characterized by an abnormal T-cell population (demon-
strated by peripheral blood lymphocyte immunophenotyping or T
cell receptor gene rearrangement studies) which may be associated
with excessive eosinophilopoietic cytokine production in vitro (e.g.,
serum interleukin-5) [15,43,44]. If none of the aforementioned condi-
tions are identified, a diagnosis HES is made if organ damage is
present.
Lymphocyte-variant HE
Some patients may exhibit expansion of a cytokine-producing,
immunophenotypically aberrant T-cell population [15,44]. The condi-
tion is a mixture of clonal and reactive processes: it is clonal with
regard to the production of abnormal T-cell lymphocytes; however,
the eosinophilia is reactive to the eosinophilopoietic growth factors
elaborated by the T-cells. These patients typically have cutaneous
signs and symptoms as the primary disease manifestation. The immu-
330 American Journal of Hematology, Vol. 89, No. 3, March 2014
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
nophenotype of these lymphocytes include double-negative, immature
T-cells (e.g., CD31CD42CD82) or absence of CD3 (e.g.,
CD32CD41), a normal component of the T-cell receptor complex
[45–47]. Additional immunophenotypic abnormalities include ele-
vated CD5 expression on CD32CD41 cells, and loss of surface CD7
and/or expression of CD27 [44]. In patients with T-cell mediated HE
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 [44,45,47–49]. In a study of 60 patients pri-
marily from dermatology clinics, 16 demonstrated circulating T-cells
with an abnormal immunophenotype [43]. 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 displayed an activated immunophenotype
(e.g., CD25 and/or HLA-DR expression). A case of lymphocyte-
variant HE was recently reported in a patient with chronic active
Epstein-Barr virus infection and an EBV-infected T-cell clone produc-
ing eosinophilopoietic cytokines. Slightly elevated EBV DNA levels
were detected in two of an additional 15 lymphocyte-variant HE
patients tested, but the causal relationship epstein barr virus (EBV)
and this subtype of eosinophilia is unclear [50].
Consensus criteria for the diagnosis of lymphocyte-variant HE
have not been established. The finding of isolated T-cell clonality by
polymerase chain reaction (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
[51]. Despite a recent study demonstrating that a high proportion of
idiopathic HES patients exhibit a clonal T-cell receptor gene rear-
rangement by PCR (18/42 patients, 43%), it is unclear whether such
clonal T-cell populations are always relevant to the disease process
[52]. Detection of elevated serum levels of TARC, a chemokine impli-
cated in Th2-mediated diseases, in addition to the finding of
increased in vitro production of cytokines from cultured peripheral
blood mononuclear cells and/or T-cells (research-based assays), may
provide additional support for a diagnosis of lymphocyte-variant HE
[19,51,53].
䊏 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% [16]. Patients usually presented with advanced
disease, 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 [21]. Factors predictive of a worse
outcome included the presence of a concurrent myeloproliferative syn-
drome, corticosteroid-refractory HE, cardiac disease, male sex, and
height of eosinophilia [21]. 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 dysfunction
(33%), infection (20%), unrelated malignancy (20%), thrombo-embolic
phenomena (13%), and vascular disease (13%) [54]. Older reports
which annotate causes of eosinophilia-related mortality are likely to be
less relevant to the current era of molecularly defined eosinophilias
where availability of targeted therapy such as imatinib, improved diag-
nostic testing, and better medical treatment and surgery for cardiovas-
cular sequelae have contributed to improved 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,
doi:10.1002/ajh.23664
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
and five of the 10 patients developed acute transformation after
median of 20 months from diagnosis [55]. Three of five patients who
did not develop AML died with active disease; one patient underwent
an allogeneic stem cell transplant and maintained a long-term remis-
sion, and the remaining patient achieved a complete remission on
imatinib and hydroxyurea [55].
In the lymphocyte-variant of HE, an indolent disease course is
usually observed. However, patients may infrequently develop either
T-cell lymphoma or Sezary syndrome, indicating this condition has
malignant potential [43]. Accumulation of cytogenetic changes (e.g.,
partial 6q and 10p deletions, trisomy 7) in T-cells, and proliferation
of lymphocytes with the CD32CD41 phenotype have been observed
with progression to lymphoma [49,56–58].
In WHO-defined myeloid malignancies, the prognostic importance
of associated eosinophilia has only been studied in few diseases. In a
series of 123 patients with SM, eosinophilia was prevalent in 34% of
cases, but was prognostically neutral and not affected by exclusion of
FIP1L1-PDGFRA-positive cases [59]. In a study of 1,008 patients with
de novo MDS, eosinophilia (and basophilia) predicted a significantly
reduced survival without having a significant impact on leukemia-free
survival [60]. 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 progno-
sis [61]. In addition, the overall survival rate was significantly lower,
and evolution to AML occurred more frequently.
䊏 Risk-Adapted Therapy
General considerations
It is difficult to predict what duration and severity of eosinophilia
will precipitate tissue damage in individual patients. Inadequate data
exist to support initiation of therapy based on a specific eosinophil
count in the absence of organ disease, although an AEC of 1,500–
2,000/mm3 has been recommended by some as a threshold for start-
ing treatment [62]. 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, and immunophenotyping), and directed organ assess-
ment (e.g., echocardiography, pulmonary function testing) to identify
occult organ disease and defined causes of eosinophilia which may
emerge after an initial diagnosis of HES [24,63,64].
Given the historically poor prognosis of chronic eosinophilic leuke-
mias and HES, and the exquisite sensitivity to imatinib in patients
with rearranged PDGFRA/B, consensus has emerged that these indi-
viduals 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, and skin), risk-adapted
therapy 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, SM, CML, and other MPNs, MDS/MPN),
therapy is dictated by disease-specific algorithms and guidelines. As a
multikinase inhibitor, imatinib has not only demonstrated remarkable
benefit in CML, but is now definitive first-line therapy 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-
doi:10.1002/ajh.23664
variant HE, which is based primarily on small case series and retro-
spective studies. The use of other chemotherapeutics for HES, and
recent investigational approaches with the anti-IL-5 antibody mepoli-
zumab and anti-CD52 antibody alemtuzumab, will also be addressed.
PDGFRA/B-Rearranged Neoplasms: The Imatinib
Experience
The success of imatinib in chronic myelogenous leukemia led to its
empiric use in patients with HE who exhibited signs suggestive of a
myeloproliferative disorder. Several case reports and small case series
of HES patients were published in 2001–2002 highlighting rapid and
complete hematologic responses (CHRs) to imatinib 100–400 mg
daily [62–66]. FIP1L1-PDGFRa was ultimately identified as the thera-
peutic target of imatinib [9,67]. The identification of the clonal
marker FIP1L1-PDGFRA in these cases operationally redefined them
as a form of chronic eosinophilic leukemia, and now comprise the
WHO major category of ’myeloid and lymphoid neoplasms with
eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 [14].
The hematologic benefit of imatinib in FIP1L1-PDGFRA-positive
myeloid neoplasms has been confirmed in numerous studies. Molecu-
lar remissions were first reported by the NIH group by PCR testing
of the peripheral blood in five of six FIP1L1-PDGFRA-positive
patients after 1–12 months of imatinib therapy [68]. Several reports
have now described rapid induction of molecular remission in
imatinib-treated FIP1L1-PDGFRA positive patients or with bone mar-
row transplantation. Although 100 mg daily may be sufficient to
achieve a molecular remission in some patients, others may require
higher maintenance doses in the range of 300–400 mg daily. Mainte-
nance dosing of 100–200 mg weekly may be sufficient to achieve a
molecular remission in some patients [69]. In a French Eosinophil
Network series, a CHR was achieved in all patients, and complete
molecular response (CMR) in 95% of patients (average starting imati-
nib dose, 165 mg/day). For 29 patients, imatinib was tapered to a
maintenance dose of 58 mg/day, permitting CHR and CMR to be
sustained [70]. The 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 1–10 months). Patients continuing ima-
tinib remained PCR-negative during a median follow-up period of 19
months (range 6–561 months). Another European study prospec-
tively assessed the natural history of molecular responses to imatinib
doses of 100–400 mg daily [3]. Among 11 patients with high pretreat-
ment transcript levels, all achieved a three-log reduction in transcript
levels by 1 year of therapy, and nine of 11 patients achieved a molec-
ular remission. In a long-term follow-up analysis of the Mayo cohort
of 18 imatinib-treated FIP1L1-PDGFRA-positive patients, one patient
with accelerated disease at presentation transformed to AML, but the
median survival of the entire cohort was not reached and the other-
wise excellent clinical outcomes corroborated the findings of other
studies [71].
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 five patients who had achieved
a stable hematologic and molecular remission at 300–400 mg daily
for at least 1 year, molecular relapse was observed in all patients after
2–5 months of either dose imatinib reduction or discontinuation [72].
American Journal of Hematology, Vol. 89, No. 3, March 2014 331
Gotlib ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

Molecular remissions could be re-established with reinduction of ima-

tinib in all cases at a dose range of 100–400 mg daily. Hematologic
relapse was noted only several weeks after discontinuation of imatinib
in four patients in a Mayo series [5]. In the French series, imatinib
was stopped in 11 patients; six of the patients subsequently relapsed,
but five remained in persistent complete hematologic or molecular
remission (range, 9–88 months) [70]. In two patients with undetect-
able FIP1L1-PDGFRA transcripts by PCR for 4 years, no evidence of
disease was detected for more than 2 years after discontinuation of
imatinib [73]. In sum, these data indicate that imatinib can effectively
suppress, but not eliminate the FIP1L1-PDGFRA clone in most
patients, although some may experience prolonged molecular remis-
sions after stoppage of imatinib. Ongoing treatment is generally rec-
ommended similar to CML guidelines, and the role of imatinib
discontinuation requires further evaluation in the context of clinical
trials.
In contrast to CML, very few cases of acquired imatinib resistance
have been reported with almost 10 years experience in treating
FIP1L1-PDGFRA-positive disease [9,74–76]. 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 analogous to the T315I BCR-ABL mutation in CML
which confers resistance to the tyrosine kinase inhibitors imatinib,
dasatinib, and nilotinib [77]. 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 [76]. Despite in vitro nanomolar activity of sorafenib,
midostaurin (PKC412), or nilotinib against the T674I mutant [78–
81], these drugs have limited clinical activity [82]. 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 [83]. In
patients with rearrangements of PDGFRB or PDGFRA variants other
than FIP1L1-PDGFRA, case reports and series indicate that imatinib,
usually given at doses of 400 mg daily, can elicit durable hematologic
and cytogenetic remissions [reviewed in [2,84]. Similar to FIP1L1-
PDGFRA, FISH can be used to assess response to imatinib in
PDGFRB-rearranged cases (Fig. 2). The natural history of patients
with myeloid/lymphoid disease with rearranged FGFR1 follows an
Figure 2. Interphase FISH results using a break-apart FISH probe for the
aggressive course usually terminating in AML in 1–2 years [14]. PDGFRB gene region in a patient with MDS/MPN with eosinophilia and an
Therefore, intensive chemotherapy with regimens such as hyper- abnormal karyotype, t(5;12)(q31-33;p13). (A) Representative interphase
CVAD (directed to treatment of T- or B-cell lymphoma), followed by nucleus demonstrating a typical abnormal signal pattern of a split red and
early allogeneic transplantation, is recommended. The data for use of green signal (corresponding to the PDGFRB gene disruption; see arrows)
and one intact red/green fusion signal (corresponding to the normal/intact
small molecule inhibitors for patients with FGFR1-rearranged disease
PDGFRB allele). 85% of nuclei were abnormal. (B) After 3 months of treat-
are sparse. The small molecule midostaurin (PKC412) inhibited the ment with imatinib and normalization of blood counts, a representative
constitutively activated ZNF198-FGFR1 fusion in vitro, as well as in a interphase nucleus demonstrates a normal FISH signal pattern with two
patient who exhibited a hematologic and cytogenetic response [85]. intact Red/Green fusion signals, indicating two intact copies of the
Although not yet formally included in the WHO category of mye- PDGFRB gene region. All cells demonstrated a normal FISH pattern. Cour-
tesy of Dr. Rhett P. Ketterling, Mayo Clinic, Rochester.
loid/lymphoid neoplasms with rearranged PDGFRA/B and FGFR1,
other recurrent genetic abnormalities have been identified in patients
with HE, including rearranged JAK2 (PCM1-JAK2 fusion) [86], and tion of imatinib [90,91]. Currently, prophylactic use of steroids during
rearranged FLT3 (ETV6-FLT3 fusion) [87]. Involvement of these the first 7–10 days of imatinib treatment is recommended for patients
genes can be surmised by reciprocal translocations on standard kar- with known cardiac disease and/or elevated serum troponin levels
yotyping (e.g., 9p24 breakpoint for JAK2 and 13q12 for FLT3). The which may be related to eosinophil-mediated heart damage or other
use of small molecule inhibitors (e.g., against JAK2 and FLT3) should cardiac comorbidities [91].
be entertained for such patients. For example, two recent reports
highlight complete hematologic remissions and cytogenetic responses Summary. Imatinib is considered definitive treatment for
(one compete and one major) in two patients with chronic eosino- PDGFRA/B-rearranged neoplasms with eosinophilia. The FDA-
philic leukemia with the PCM1-JAK2 fusion [t(8;9)(p22;p24)] treated recommended starting dose for patients with the FIP1L1-PDGFRA
with the JAK 1/2 inhibitor ruxolitinib [88,89]. rearrangement is 100 mg daily. Cumulative data with long-term
Imatinib’s safety profile in eosinophilic disorders parallels the follow-up indicate that this dose is sufficient to elicit complete and
drug’s good tolerability in CML. A few cases of cardiogenic shock durable hematologic and complete molecular remissions. For patients
have been reported in FIP1L1-PDGFRA-positive patients after initia- with myeloid neoplasms (usually MDS/MPNs) with eosinophilia and

332 American Journal of Hematology, Vol. 89, No. 3, March 2014 doi:10.1002/ajh.23664
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
rearranged PDGFRB, the recommended dose is 400 mg daily which
reflects the dose consistently used in several case series with excellent
outcomes.
Treatment of HES and CEL, NOS: corticosteroids,
hydroxyurea, and interferon-alpha
For patients with strictly defined HES (e.g., exclusion of all other
possible causes of HE), corticosteroids (e.g., prednisone 1 mg/kg) are
the mainstay of therapy and are effective in producing rapid reduc-
tions in the eosinophil count. However, therapy can be complicated
by side effects in those patients requiring long-term treatment to sup-
press eosinophilia and organ damage. In a retrospective analysis, 141/
188 (75%) HES patients received corticosteroids as initial monother-
apy with 85% of these individuals achieving a complete or partial
response after 1 month of treatment [19]. 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 reso-
lution of eosinophilia, five patients (15%) achieved a 50% reduction,
and seven patients (21%) were resistant or intolerant to corticoste-
roids [92]. With symptom control and reduction of the eosinophil
count to below 1,500/mm3, corticosteroids can usually be tapered.
Recrudescence of symptoms, signs of organ damage, and/or signifi-
cant 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 nonresponders
[18,24,93]. A typical starting dose is 500–1,000 mg daily. Hydrox-
yurea was used in 64/188 patients (34%) in the retrospective study;
among 18 patients receiving hydroxuyrea as monotherapy, 13 patients
(72%) achieved a complete or partial response [18]. When hydrox-
yurea 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 [94–100], or can be used in
conjunction with corticosteroids as a steroid-sparing agent for indi-
viduals requiring higher doses of prednisone. Some have advocated
its use as initial therapy for these disorders [99]. In the retrospective
study, 46/188 patients were treated with IFN-a (mostly in combina-
tion with glucocorticoids) with response rates of 50 and 75% as
monotherapy or combination 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 maintain a remission [101]. Initiation of therapy
at one million units by subcutaneous injection thrice weekly (tiw)
and gradual escalation of the dose to 3–4 million units tiw or higher
may be required to control HE in some patients. Remissions have
been associated with improvement in clinical symptoms and organ
disease, including hepatosplenomegaly [95,99], cardiac and throm-
boembolic complications [94,96], mucosal ulcers [97], and skin
involvement [100]. Treatment of four HES patients with PEG-IFN-a-
2b among a larger cohort of BCR-ABL-negative MPN cohort resulted
in one complete and one partial response, but side effects required
that the initial study dose be reduced from 3 to 2 mcg/kg/week [102].
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 [103,104]. Side effects of short- and longer-acting for-
mulations of IFN-a are usually dose dependent and include fatigue
doi:10.1002/ajh.23664
and flu-like symptoms, transaminitis, cytopenias, depression, hypo-
thyroidism, 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 [105–107], cyclophosphamide [108], and
etoposide [109,110]. Responses to 2-chlorodeoxyadenosine alone
[111] or in combination with cytarabine [112], and cyclosporin-A
[113,114] have also been reported in HES, with a discontinuation rate
of 82% with CSA in one series due to poor tolerance [19].
In selected cases, patients with CEL, NOS, or HES may benefit
from imatinib, usually administered at higher doses (>400 mg daily)
[115]. 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
[116]. Clinical trials with novel agents should always be considered.
Summary. Corticosteroids are potent antieosinophil agents with
established efficacy in HES and should be considered first-line treat-
ment. Similar to its use in other MPNs, hydroxyurea can serve as
effective palliative chemotherapy to control leukocytosis and eosino-
philia, but with no proven role in favorably altering the natural his-
tory 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. 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.
Treatment of lymphocyte-variant HE
Patients with clonal population(s) of T-cells with an aberrant
immunophenotype 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. Hydroxyurea and imatinib
are less likely to demonstrate efficacy in this lymphocyte-variant of
HE compared 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 HE [19].
Summary. Corticosteroids are first-line therapy in patients with
HE in whom a clonal population of T-cells with an abnormal immu-
nophenotype are identified and other causes of an elevated eosinophil
count are excluded.
Antibody approaches for HES
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 antibody that inhibits binding of IL-5 to the a chain
of the IL-5 receptor expressed on eosinophils [117]. In HES patients,
regression of constitutional symptoms, eosinophilic dermatologic
lesions, and improvements FEV1 measurements in individuals with
pulmonary disease have been observed with anti-IL-5 antibody ther-
apy [118–120]. Among the few patients studied, response has not
been predicted by pretreatment serum IL-5 levels or presence of
FIP1L1-PDGFRA. Rebound eosinophilia, 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 neu-
tralizing antibodies [116]. In the largest study of HES patients to
American Journal of Hematology, Vol. 89, No. 3, March 2014 333
Gotlib
date, the safety and steroid-sparing effects of mepolizumab was eval-
uated in a randomized, double-blind, placebo-controlled trial of 85
FIP1L1-PDGFRA-negative patients [121]. Blood eosinophil levels were
stabilized at <1,000 cells/mm3 on 20–60 mg/day prednisone during a
run-in period of up to 6 weeks. Patients were subsequently random-
ized to intravenous mepolizumab 750 mg or placebo every 4 weeks
for 36 weeks. No adverse events were significantly more frequent
with mepolizumab compared to placebo. A significantly higher pro-
portion 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 pred-
nisone free without other HES medications for 12 consecutive
weeks [122]. Mepolizumab is not currently approved by the FDA, but
is currently available on a compassionate use basis (ClinicalTrials.gov
Identifier 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 [123]. In a double-blind, placebo-controlled,
randomized trial, reslizumab significantly reduced intraepithelial
esophageal eosinophil counts in children and adolescents with eosino-
philic esophagitis, but symptom improvement was observed in both
treatment groups [124].
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 [78]. In con-
trast, 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 [125].
Alemtuzumab. Alemtuzumab is an anti-CD52 monoclonal anti-
body that has been evaluated in idiopathic HES based on expression of
the CD52 antigen on eosinophils [126,127]. 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 hema-
tologic remission (CHR) in 10/12 subjects (83%), with two patients
achieving a partial remission. Patients with CHR who received mainte-
nance alemtuzumab therapy exhibited significantly longer time to pro-
gression than patients who were only observed. Eleven patients
relapsed (only one while on maintenance), and six were rechallenged
with alemtuzumab. Five (83%) achieved second CHR after a median of
3.5 weeks, for a median duration of 123 weeks [128,129].
Summary. Use of anti-IL-5 and anti-CD52 antibody approaches
in the treatment of HES remain investigational. Potential benefits
include resolution of eosinophilia and disease-related symptomology,
and a steroid-sparing effect (mepolizumab). However, with discontin-
uation of therapy, benefits appear to be short lived and the potential
for rebound eosinophilia exists. Maintenance therapy with these anti-
bodies is generally required to sustain responses.
Transplantation
Bone marrow/peripheral blood stem cell allogeneic transplantation
has been attempted in patients with aggressive disease. Disease-free
survival ranging from 8 months to 5 years has been reported [130–
334 American Journal of Hematology, Vol. 89, No. 3, March 2014
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
134] with one patient relapsing at 40 months [135]. Allogeneic trans-
plantation 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 [136,137]. 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 [138]. Despite success in selected cases, the role of trans-
plantation in HES is not well established.
Supportive care and surgery
Leukapheresis can elicit transient reductions in high leukocyte and
eosinophil counts, but is not an effective maintenance therapy [139–
141]. Similar to other MPNs, splenectomy has been performed for
hypersplenism-related abdominal pain and splenic infarction, but is
not considered standard treatment [20,142]. Anticoagulants and anti-
platelet agents have demonstrated variable success in preventing
recurrent thromboembolism [20,143,144].
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 [18,24], Mitral and/or
tricuspid valve repair or replacement [145–149] and endomyocardec-
tomy for late-stage fibrotic heart disease [146,150] can improve car-
diac function. Bioprosthetic devices are generally preferred over their
mechanical counterparts because of the reduced frequency of valve
thrombosis.
䊏 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 prog-
nosis of patients previously diagnosed as “HES” and who likely repre-
sented a significant portion of older series of patients who exhibited a
poor prognosis. Corticosteroids, interferon-alpha, hydroxyurea/other
chemotherapy, and targeted antibodies can elicit clinical benefit in
the primary 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 eval-
uated in phase I-III trials of myelofibrosis) may have a role in
patients with eosinophilic disease. For example, rare patients with HE
have been found to carry the JAK2 V617F activating mutation
[151,152]. More germane to eosinophil biology is the finding that the
JAK2 pathway mediates antiapoptosis signals in eosinophils in
response to GM-CSF and IL-5 [153,154] in addition to FIP1L1-
PDGFRa [155]. 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 onco-
genes skew proliferation and differentiation toward the eosinophil lin-
eage in a process that requires NF-jB suggests the possibility for new
treatments that target this pathway [156].
䊏 Acknowledgment
Dr. Gotlib thanks Jenny Ma for her editorial assistance.
doi:10.1002/ajh.23664
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
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