Biologic

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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C 2014 Wiley Periodicals, Inc.
V
doi:10.1002/ajh.00032 American Journal of Hematology, Vol. 89, No. 3, March 2014 325
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:
[email protected]
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.

V
326 American Journal of Hematology, Vol. 89, No. 3, March 2014 doi:10.1002/ajh.23664
the overwhelming majority of patients with FIP1L1-PDGFRA or mye- syndrome (MDS), systemic mastocytosis (SM), classic MPNs (chronic
loproliferative variants of HES are male [3,9,10], whereas other eosin- myeloid leukemia, polycythemia vera, essential thrombocythemia, and
ophilia subtypes exhibit no clear gender bias. primary myelofibrosis), and MDS/MPN overlap disorders (e.g.,
chronic myelomonocytic leukemia, CMML; Table II). CEL-NOS is
Definition of eosinophilia and classification histologically characterized by an increase in blasts in the bone mar-
row or blood (but fewer than 20% to exclude acute leukemia as a
The upper limit of normal for the range of % eosinophils in the diagnosis), and/or there is an evidence for clonality in the eosinophil
peripheral blood is 3–5% with a corresponding absolute eosinophil lineage [15]. A diagnosis of idiopathic HES requires exclusion of all
count (AEC) of 350–500/mm3 [11,12]. The severity of eosinophilia primary and secondary causes of hypereosinophilia as well as
has been arbitrarily divided into mild (AEC from the upper limit of lymphocyte-variant HE (Table II). The modern definition of HES
normal to 1,500/mm3), moderate (AEC 1,500–5,000/mm3), and severe remains a vestige of the historical criteria outlined by Chusid et al. in
(AEC > 5,000/mm3) [11–13]. 1975: the AEC is >1,500/mm3 for more than 6 months, and tissue
The classification of eosinophilic diseases was revised in the 2008 damage is present [16]. The requirement that eosinophilia persist for
World Health Organization scheme of myeloid neoplasms (Table I). more than 6 months is less consistently embraced today because of
In recognition of the growing list of recurrent, molecularly defined the availability of more sophisticated tools to rapidly evaluate eosino-
primary eosinophilias, a new major category was created, “Myeloid philia and the need for some patients to receive expedited treatment
and lymphoid neoplasms with eosinophilia and abnormalities of to minimize organ damage. In contrast to “HES,” “idiopathic HE” is
platelet-derived growth factor receptor alpha (PDGFRA), platelet- the preferred term when end-organ damage is absent [15]. The pool
derived growth factor receptor beta (PDGFRB), or fibroblast growth of classically defined idiopathic HES patients has diminished due to
factor receptor 1 (FGFR1)” (Table I) [14]. Within the major WHO an increasing proportion of cases which have been reassigned as clo-
category of myeloproliferative neoplasms (MPNs), “chronic eosino- nal marrow disorders. HES may therefore be considered a provisional
philic leukemia-not otherwise specified” (CEL-NOS) is one of eight diagnosis until a primary or secondary cause of eosinophilia is
disease entities within this group (Table I) [15]. CEL-NOS is opera- recognized.
tionally defined by absence of the Philadelphia chromosome or a In 2011, the Working Conference on Eosinophil Disorders and
rearrangement involving PDGFRA/B and FGFR1, and the exclusion of Syndromes proposed a new terminology for eosinophilic syndromes
other acute or chronic primary marrow neoplasms associated with [17]. The panel recommended the higher level term “HE” for persis-
eosinophilia such as acute myeloid leukemia (AML), myelodysplastic tent and marked eosinophilia (AEC > 1,500/mm3). In turn, HE sub-
types were divided into a hereditary (familial) variant (HEFA), HE of
TABLE I. 2008 World Health Organization (WHO) Classification of Myeloid undetermined significance (HEUS), primary (clonal/neoplastic) HE
Malignancies 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
1. Acute myeloid leukemia and related disorders
2. Myeloproliferative neoplasms (MPN) damage is referred to as “HES” with specific variants designated by
Chronic myelogenous leukemia, BCR-ABL1 positive subscripts (e.g., HESUS, HESN, and HESR). Additional recommenda-
Chronic neutrophilic leukemia tions advanced by the consensus panel are summarized in their
Polycythemia vera report.
Primary myelofibrosis
Essential thrombocythemia
Chronic eosinophilic leukemia, not otherwise specified
Mastocytosis
Clinical presentation and diagnosis
Myeloproliferative neoplasms, unclassifiable The varied clinical presentations of primary eosinophilias/HES
3. Myelodysplastic syndromes (MDS) reflect their heterogeneous pathophysiology. In two retrospective
Refractory cytopenia with uni-lineage dysplasia
䊏 Refractory anemia
series published in 1982 and 2009, eosinophilia was an incidental
䊏 Refractory neutropenia finding in 12 and 6% of patients, respectively [18,19]. The most com-
䊏 Refractory thrombocytopenia mon presenting signs and symptoms were weakness and fatigue
Refractory anemia with ring sideroblasts (26%), cough (24%), dyspnea (16%), myalgias or angioedema (14%),
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blasts (RAEB)
rash or fever (12%), and rhinitis (10%) [17]. In HES, leukocytosis
䊏 RAEB-1
(e.g., 20,000–30,000/mm3 or higher) with peripheral eosinophilia in
䊏 RAEB-2 the range of 30–70% is a common finding [16,18–20]; the aforemen-
Myelodysplastic syndrome with isolated del(5q) tioned retrospective analysis of 188 patients from 2009 observed a
Myelodysplastic syndrome, unclassifiable mean peak eosinophil count of 6,600/mm3 with a range of 1,500–
4. MDS/MPN
Chronic myelomonocytic leukemia 400,000/mm3 [18]. Other hematologic findings include peripheral
䊏 CMML-1 blood or bone marrow neutrophilia, basophilia, myeloid immaturity,
䊏 CMML-2 and both mature and immature eosinophils with varying degrees of
Atypical chronic myeloid leukemia, BCR-ABL1 negative dysplasia [20–22]. In one series, anemia was present in 53% of patients,
Juvenile myelomonocytic leukemia
MDS/MPN, unclassifiable
thrombocytopenia was more common than thrombocytosis (31% vs.
䊏 Refractory anemia with ring sideroblasts and
16%), and bone marrow eosinophilia ranged from 7 to 57% (mean
thrombocytosis (RARS-T) 33%) [22]. Marrow findings of Charcot–Leyden crystals, and some-
5. Myeloid and lymphoid neoplasms associated with eosinophilia and times increased blasts and marrow fibrosis, are also observed [22].
abnormalities of PDGFRA, PDGFRB, or FGFR1 Essentially all organ systems may be susceptible to the effects of
Myeloid and lymphoid neoplasms associated with PDGFRA
rearrangement sustained eosinophilia [reviewed in 23]. During follow-up of patients
Myeloid neoplasms associated with PDGFRB rearrangement with HE, dermatologic involvement was also the most common clini-
Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities. cal manifestation reported in 69% of patients, followed by pulmonary
(44%) and gastrointestinal (38%) manifestations. Cardiac disease
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 [e.g., Churg–Strauss Syndrome, granulomatosis with polyangiitis
eventually identified in 20% of patients (only 6% at the time of initial (Wegener’s), systemic lupus erythematosus], pulmonary eosinophilic
presentation) [19]. Progressive heart failure is a proto-typical example diseases (e.g., idiopathic acute or chronic eosinophilia pneumonia, trop-
of eosinophil-mediated organ injury. It involves a multistep patho- ical pulmonary eosinophilia, allergic bronchopulmonary aspergillosis,
physiological process involving eosinophil infiltration of cardiac tissue etc.), allergic gastroenteritis (with associated peripheral eosinophilia),
and release of toxic mediators from eosinophils [reviewed in 18,24]. and metabolic conditions such as adrenal insufficiency are diagnostic
Endocardial damage with resulting platelet thrombus can lead to considerations in the appropriate clinical context [28–30]. Nonmyeloid
mural thrombi and increased embolic risk. In the later fibrotic stage, malignancies may be associated with secondary eosinophilia which
fibrous thickening of the endocardial lining can evolve to a restrictive results from the production of cytokines such as IL-3, IL-5, and GM-
cardiomyopathy [18,24]. Valvular insufficiency results from mural CSF which promote eosinophil differentiation and survival. For exam-
endocardial thrombosis and fibrosis involving leaflets of the mitral or ple, these cytokines may be elaborated from malignant cells in T-cell
tricuspid valves [25–27]. 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
䊏 Diagnosis Syndrome, Omenn Syndrome, episodic angioedema and eosinophilia
(Gleich’s syndrome), and eosinophilia-myalgia syndrome (e.g., possibly
Step 1: Exclude secondary (reactive) causes of
related to tryptophan ingestion, or of historical interest, the epidemic of
eosinophilia toxic-oil syndrome) [17]. Repeated ova and parasite testing, stool cul-
Secondary eosinophilia has numerous causes which may require ture, and antibody testing for specific parasites (e.g., Strongyloides) is
diagnostic evaluation by a cadre of different subspecialty consultants. paramount for identifying infectious etiologies in the appropriate clini-
In developing countries, eosinophilia most commonly derives from cal context. Additional laboratory and imaging tests (e.g., chest-x-ray,
infections, particularly tissue-invasive parasites [13]. Allergy/atopy and electrocardiogram and echocardiography, CT scan of the chest, abdo-
hypersensitivity conditions, drug reaction, collagen-vascular disease men/pelvis) are guided by the patient’s travel history, presenting
Figure 1. Diagnostic and treatment algorithm based on 2008 WHO classification of eosinophilic disorders.
symptoms, and findings on physical examination. For eosinophilic lung loid neoplasm such as SM, chronic myelogenous leukemia, acute
diseases, pulmonary function testing, bronchoscopy, serologic tests [e.g., myelogenous leukemia (especially the historically defined M2 and M4
aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis Eo French-American-British subtypes), MDS, or MDS/MPN overlap
(ABPA)] may be obtained to further characterize lung involvement. 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
Step 2: Evaluate for primary (clonal) eosinophilia malignancies because of clinicopathologic similarity to CML and the
If secondary causes of eosinophilia are excluded, the work-up BCR-ABL-negative MPNs [9,23].
should proceed to the evaluation of a primary bone marrow disorder. Laboratory evaluation of primary eosinophilia should begin with
Examination of the blood smear and blood tests (e.g., circulating screening of the peripheral blood for the FIP1L1-PDGFRA gene
blasts, dysplastic cells, monocytosis, elevated serum B12, or tryptase fusion (by RT-PCR or interphase/metaphase FISH; Fig. 1). FISH
level) in conjunction with bone marrow morphologic, cytogenetic, probes that hybridize to the region between the FIP1L1 and PDGFRA
and immunophenoytpic analysis will help ascertain whether the dif- genes are used to detect the presence of the cytogenetically occult
ferential diagnosis of eosinophilia includes a well-defined WHO mye- 800-kb deletion on 4q12 that results in FIP1L1-PDGFRA [9,34]. As
the CHIC2 gene is located in this deleted genetic segment, this widely nophenotype of these lymphocytes include double-negative, immature
available clinical test is referred to as “FISH for the CHIC2 deletion” T-cells (e.g., CD31CD42CD82) or absence of CD3 (e.g.,
[34]. In instances where FIP1L1-PDGFRA screening is not available, CD32CD41), a normal component of the T-cell receptor complex
evaluation of the serum tryptase can be a useful surrogate marker for [45–47]. Additional immunophenotypic abnormalities include ele-
FIP1L1-PDGFRA-positive disease as increased levels segregate with vated CD5 expression on CD32CD41 cells, and loss of surface CD7
this molecular abnormality and myeloproliferative variants of HE and/or expression of CD27 [44]. In patients with T-cell mediated HE
[35]. FIP1L1-PDGFRA has also been identified histopathologically with elevated IgE levels, lymphocyte production of IL-5, and in some
defined cases of SM with associated eosinophilia [4]. The bone mar- cases IL-4 and IL-13, suggests that these T-cells have a helper type 2
rows of such patients typically exhibit less dense clusters of mast cells (Th2) cytokine profile [44,45,47–49]. In a study of 60 patients pri-
by tryptase immunostaining are observed in SM with the highly prev- marily from dermatology clinics, 16 demonstrated circulating T-cells
alent KIT D816V mutation [4]. The FIP1L1-PDGFRA fusion has also with an abnormal immunophenotype [43]. Clonal rearrangement of
been found in cases of AML and T-cell lymphoblastic lymphoma T-cell receptor genes was demonstrated in half of these individuals
associated with eosinophilia [36]. In addition to dysregulation of (8/60 total patients). The abnormal T-cells secreted high levels of
PDGFRA by fusion to FIP1L1 or other partner genes, activating point interleukin-5 in vitro, and displayed an activated immunophenotype
mutations have been identified in PDGFRA in patients with HE [37]. (e.g., CD25 and/or HLA-DR expression). A case of lymphocyte-
Although there was variability in their transforming ability, injection variant HE was recently reported in a patient with chronic active
of cells harboring these mutants into mice induced a leukemia-like Epstein-Barr virus infection and an EBV-infected T-cell clone produc-
disease. Imatinib treatment significantly decreased leukemic growth ing eosinophilopoietic cytokines. Slightly elevated EBV DNA levels
and prolonged survival [37]. were detected in two of an additional 15 lymphocyte-variant HE
Absence of the FIP1L1-PDGFRA fusion should prompt evaluation patients tested, but the causal relationship epstein barr virus (EBV)
for other primary eosinophilias associated with recurrent molecular and this subtype of eosinophilia is unclear [50].
abnormalities. Molecular evidence for a PDGFRA, PDGFRB, or Consensus criteria for the diagnosis of lymphocyte-variant HE
FGFR1 fusion gene is often accompanied by its abnormal karyotype have not been established. The finding of isolated T-cell clonality by
equivalent: rearrangement of 4q12 (PDGFRA fusion partners besides polymerase chain reaction (PCR) without T-cell immunophenotypic
FIP1L1), 5q31-33 (PDGFRB), or 8p11-13 (FGFR1) [14]. Despite the abnormalities or demonstration of Th2 cytokine production is not
rare frequency (<1%) of PDGFRB-rearrangements in cytogenetically felt to be sufficient to make a diagnosis of this eosinophilia variant
defined cases of CMML and other myeloid neoplasms (e.g., atypical [51]. Despite a recent study demonstrating that a high proportion of
CML, juvenile myelomonocytic leukemia, MDS/MPN overlap disor- idiopathic HES patients exhibit a clonal T-cell receptor gene rear-
ders), their identification is critical given their responsiveness to ima- rangement by PCR (18/42 patients, 43%), it is unclear whether such
tinib [38]. Over 20 gene fusion partners of PDGFRB have been clonal T-cell populations are always relevant to the disease process
described. Eosinophilic myeloid neoplasms related to fusions involv- [52]. Detection of elevated serum levels of TARC, a chemokine impli-
ing the FGFR1 gene are similarly rare [14]. In these cases, the associa- cated in Th2-mediated diseases, in addition to the finding of
tion of t(8p11-13) breakpoint with lymphoblastic lymphoma with increased in vitro production of cytokines from cultured peripheral
eosinophilia and myeloid hyperplasia was first described in 1995, and blood mononuclear cells and/or T-cells (research-based assays), may
was previously referred to as “8p11 myeloproliferative syndrome” or provide additional support for a diagnosis of lymphocyte-variant HE
“stem cell leukemia/lymphoma.” Following the discovery of the [19,51,53].
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- 䊏 Risk Stratification
philias should lend consideration to a diagnosis of CEL-NOS when Older case series indicate that lives of patients with HES were over-
there is cytogenetic and/or morphologic evidence of a eosinophilic shadowed by early cardiac death. A review of 57 HES cases published
myeloid malignancy that is otherwise not classifiable [15]. CEL-NOS through 1973 reported a median survival of 9 months and the 3-year
may be distinguished from HES by the presence of a nonspecific clo- survival was only 12% [16]. Patients usually presented with advanced
nal cytogenetic abnormality or increased blast cells (>2% in the disease, with congestive heart failure accounting for 65% of deaths at
peripheral blood or >5% in the bone marrow, but <20% blasts in autopsy. In addition to cardiac disease, peripheral blood blasts or a
both compartments). Lymphocyte-variant HE is a more obscure diag- WBC count greater than 100,000/mm3 were poor prognostic factors
nostic entity characterized by an abnormal T-cell population (demon- [16]. A later report of 40 HES patients cited a 5-year survival rate of
strated by peripheral blood lymphocyte immunophenotyping or T 80%, decreasing to 42% at 15 years [21]. Factors predictive of a worse
cell receptor gene rearrangement studies) which may be associated outcome included the presence of a concurrent myeloproliferative syn-
with excessive eosinophilopoietic cytokine production in vitro (e.g., drome, corticosteroid-refractory HE, cardiac disease, male sex, and
serum interleukin-5) [15,43,44]. If none of the aforementioned condi- height of eosinophilia [21]. A recent retrospective review of 247 HES
tions are identified, a diagnosis HES is made if organ damage is patients at the Mayo Clinic identified 23 subjects who died during the
present. 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
Lymphocyte-variant HE phenomena (13%), and vascular disease (13%) [54]. Older reports
Some patients may exhibit expansion of a cytokine-producing, which annotate causes of eosinophilia-related mortality are likely to be
immunophenotypically aberrant T-cell population [15,44]. The condi- less relevant to the current era of molecularly defined eosinophilias
tion is a mixture of clonal and reactive processes: it is clonal with where availability of targeted therapy such as imatinib, improved diag-
regard to the production of abnormal T-cell lymphocytes; however, nostic testing, and better medical treatment and surgery for cardiovas-
the eosinophilia is reactive to the eosinophilopoietic growth factors cular sequelae have contributed to improved survival.
elaborated by the T-cells. These patients typically have cutaneous The prognosis of WHO-defined CEL-NOS is poor. In a recently
signs and symptoms as the primary disease manifestation. The immu- reported cohort of 10 patients, the median survival was 22.2 months,
and five of the 10 patients developed acute transformation after variant HE, which is based primarily on small case series and retro-
median of 20 months from diagnosis [55]. Three of five patients who spective studies. The use of other chemotherapeutics for HES, and
did not develop AML died with active disease; one patient underwent recent investigational approaches with the anti-IL-5 antibody mepoli-
an allogeneic stem cell transplant and maintained a long-term remis- zumab and anti-CD52 antibody alemtuzumab, will also be addressed.
sion, and the remaining patient achieved a complete remission on
imatinib and hydroxyurea [55].
PDGFRA/B-Rearranged Neoplasms: The Imatinib
In the lymphocyte-variant of HE, an indolent disease course is
usually observed. However, patients may infrequently develop either Experience
T-cell lymphoma or Sezary syndrome, indicating this condition has The success of imatinib in chronic myelogenous leukemia led to its
malignant potential [43]. Accumulation of cytogenetic changes (e.g., empiric use in patients with HE who exhibited signs suggestive of a
partial 6q and 10p deletions, trisomy 7) in T-cells, and proliferation myeloproliferative disorder. Several case reports and small case series
of lymphocytes with the CD32CD41 phenotype have been observed of HES patients were published in 2001–2002 highlighting rapid and
with progression to lymphoma [49,56–58]. complete hematologic responses (CHRs) to imatinib 100–400 mg
In WHO-defined myeloid malignancies, the prognostic importance daily [62–66]. FIP1L1-PDGFRa was ultimately identified as the thera-
of associated eosinophilia has only been studied in few diseases. In a peutic target of imatinib [9,67]. The identification of the clonal
series of 123 patients with SM, eosinophilia was prevalent in 34% of marker FIP1L1-PDGFRA in these cases operationally redefined them
cases, but was prognostically neutral and not affected by exclusion of as a form of chronic eosinophilic leukemia, and now comprise the
FIP1L1-PDGFRA-positive cases [59]. In a study of 1,008 patients with WHO major category of ’myeloid and lymphoid neoplasms with
de novo MDS, eosinophilia (and basophilia) predicted a significantly eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 [14].
reduced survival without having a significant impact on leukemia-free The hematologic benefit of imatinib in FIP1L1-PDGFRA-positive
survival [60]. A retrospective of 288 individuals with newly diagnosed myeloid neoplasms has been confirmed in numerous studies. Molecu-
MDS, revealed that significantly higher numbers of patients with lar remissions were first reported by the NIH group by PCR testing
eosinophilia or basophilia (compared to patients with neither) had of the peripheral blood in five of six FIP1L1-PDGFRA-positive
chromosomal abnormalities carrying an intermediate or poor progno- patients after 1–12 months of imatinib therapy [68]. Several reports
sis [61]. In addition, the overall survival rate was significantly lower, have now described rapid induction of molecular remission in
and evolution to AML occurred more frequently. 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
䊏 Risk-Adapted Therapy 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
General considerations molecular remission in some patients [69]. In a French Eosinophil
It is difficult to predict what duration and severity of eosinophilia Network series, a CHR was achieved in all patients, and complete
will precipitate tissue damage in individual patients. Inadequate data molecular response (CMR) in 95% of patients (average starting imati-
exist to support initiation of therapy based on a specific eosinophil nib dose, 165 mg/day). For 29 patients, imatinib was tapered to a
count in the absence of organ disease, although an AEC of 1,500– maintenance dose of 58 mg/day, permitting CHR and CMR to be
2,000/mm3 has been recommended by some as a threshold for start- sustained [70]. The optimal imatinib dose which sustains a molecular
ing treatment [62]. Treatment algorithms have incorporated serial remission has not been defined.
monitoring of eosinophil counts, bone marrow aspiration and biopsy The natural history of imatinib-treated FIP1L1-PDGFRA-positive
with cytogenetics, evaluation of clonality (e.g., T-cell receptor gene myeloid neoplasms was evaluated in an Italian prospective cohort of
rearrangement, and immunophenotyping), and directed organ assess- 27 patients with a median follow-up period of 25 months (range 15–
ment (e.g., echocardiography, pulmonary function testing) to identify 60 months) [10]. Patients were dose escalated from an initial dose of
occult organ disease and defined causes of eosinophilia which may 100 mg daily to a final dose of 400 mg daily. Complete hematologic
emerge after an initial diagnosis of HES [24,63,64]. remission was achieved in all patients within 1 month, and all
Given the historically poor prognosis of chronic eosinophilic leuke- patients became PCR negative for FIP1L1-PDGFRA after a median of
mias and HES, and the exquisite sensitivity to imatinib in patients 3 months of treatment (range 1–10 months). Patients continuing ima-
with rearranged PDGFRA/B, consensus has emerged that these indi- tinib remained PCR-negative during a median follow-up period of 19
viduals be treated in the absence of organ dysfunction. Proactive months (range 6–561 months). Another European study prospec-
treatment has the potential to not only forestall tissue damage but tively assessed the natural history of molecular responses to imatinib
also to achieve complete molecular remissions. doses of 100–400 mg daily [3]. Among 11 patients with high pretreat-
In patients with eosinophilia-related organ damage (e.g., heart, ment transcript levels, all achieved a three-log reduction in transcript
lungs, gastrointestinal, central nervous system, and skin), risk-adapted levels by 1 year of therapy, and nine of 11 patients achieved a molec-
therapy rests on the premise of identifying the specific WHO-defined ular remission. In a long-term follow-up analysis of the Mayo cohort
eosinophilic disorder and individualizing treatment accordingly. For of 18 imatinib-treated FIP1L1-PDGFRA-positive patients, one patient
patients with an eosinophilia-associated WHO defined myeloid malig- with accelerated disease at presentation transformed to AML, but the
nancy (e.g., AML, MDS, SM, CML, and other MPNs, MDS/MPN), median survival of the entire cohort was not reached and the other-
therapy is dictated by disease-specific algorithms and guidelines. As a wise excellent clinical outcomes corroborated the findings of other
multikinase inhibitor, imatinib has not only demonstrated remarkable studies [71].
benefit in CML, but is now definitive first-line therapy in patients Although in-depth and durable molecular responses occur with
with FIP1L1-PDGFRA-positive disease, and the rare patients with imatinib, discontinuation of the drug can lead to relapse [3,10]. In a
alternate PDGFRA fusions or rearranged PDGFRB. The discussion of dose de-escalation trial of imatinib in five patients who had achieved
treatment options below will focus on the experience with imatinib in a stable hematologic and molecular remission at 300–400 mg daily
PDGFRA/B-rearranged neoplasms and separately the therapeutic for at least 1 year, molecular relapse was observed in all patients after
options available for patients with CEL, NOS, HES, and lymphocyte- 2–5 months of either dose imatinib reduction or discontinuation [72].
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
rearranged PDGFRB, the recommended dose is 400 mg daily which and flu-like symptoms, transaminitis, cytopenias, depression, hypo-
reflects the dose consistently used in several case series with excellent thyroidism, and peripheral neuropathy. Unlike hydroxyurea which is
outcomes. 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
Treatment of HES and CEL, NOS: corticosteroids,
etoposide [109,110]. Responses to 2-chlorodeoxyadenosine alone
hydroxyurea, and interferon-alpha [111] or in combination with cytarabine [112], and cyclosporin-A
For patients with strictly defined HES (e.g., exclusion of all other [113,114] have also been reported in HES, with a discontinuation rate
possible causes of HE), corticosteroids (e.g., prednisone 1 mg/kg) are of 82% with CSA in one series due to poor tolerance [19].
the mainstay of therapy and are effective in producing rapid reduc- In selected cases, patients with CEL, NOS, or HES may benefit
tions in the eosinophil count. However, therapy can be complicated from imatinib, usually administered at higher doses (>400 mg daily)
by side effects in those patients requiring long-term treatment to sup- [115]. However, hematologic responses in this group are more often
press eosinophilia and organ damage. In a retrospective analysis, 141/ partial, short lived, and may reflect drug-related myelosuppression
188 (75%) HES patients received corticosteroids as initial monother- [9,10]. Rare complete responses may represent diagnostically occult
apy with 85% of these individuals achieving a complete or partial PDGFRA or PDGFRB mutations or other unknown pathogenetic targets
response after 1 month of treatment [19]. In this series, the median [116]. Clinical trials with novel agents should always be considered.
maximal dose was 40 mg (5–625 mg), the median maintenance dose Summary. Corticosteroids are potent antieosinophil agents with
was 10 mg daily (range 1–40 mg daily) and the duration of therapy established efficacy in HES and should be considered first-line treat-
ranged from 2 months to 20 years. In another retrospective series, the ment. Similar to its use in other MPNs, hydroxyurea can serve as
median starting dose of prednisone was 30 mg daily (range 5–85 effective palliative chemotherapy to control leukocytosis and eosino-
mg), and the maintenance dose ranged from 5 mg twice weekly to 60 philia, but with no proven role in favorably altering the natural his-
mg daily. Twenty-one of 33 patients (64%) exhibited a complete reso- tory of HES or CEL, NOS. Based on a limited published literature,
lution of eosinophilia, five patients (15%) achieved a 50% reduction, IFN-a has demonstrated hematologic responses and reversion of
and seven patients (21%) were resistant or intolerant to corticoste- organ injury in patients with HES and CEL. The logic of using IFN-a
roids [92]. With symptom control and reduction of the eosinophil in CEL is partly extrapolated from its efficacy in other MPNs such as
count to below 1,500/mm3, corticosteroids can usually be tapered. CML, as well as PV and ET, and evidence for cytogenetic remitting
Recrudescence of symptoms, signs of organ damage, and/or signifi- activity. Although typically used as a second-line agent in HES steroid
cant increase of the eosinophil count with a prednisone dose >10 mg failures, IFN-a could be used as initial therapy in patients with
daily is an indication for addition of other agents. contra-indications or intolerance to steroid therapy. The optimal dose
Hydroxyurea is an effective first-line agent for HES which may be and duration of IFN-a therapy in HES is unknown and is tailored to
used in conjunction with corticosteroids or in steroid nonresponders individual response and tolerability.
[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; Treatment of lymphocyte-variant HE
among 18 patients receiving hydroxuyrea as monotherapy, 13 patients Patients with clonal population(s) of T-cells with an aberrant
(72%) achieved a complete or partial response [18]. When hydrox- immunophenotype and/or cytokine production should initially be
yurea was combined with corticosteroids, the overall response rate treated with corticosteroids. Patients who are refractory to therapy or
was 69%. exhibit relapse may be considered for treatment with IFN-a or
Interferon-a (IFN-a) can produce hematologic and cytogenetic steroid-sparing immunosuppressive agents. Hydroxyurea and imatinib
remissions in HES and CEL patients refractory to other therapies are less likely to demonstrate efficacy in this lymphocyte-variant of
including prednisone and/or hydroxyurea [94–100], or can be used in HE compared to myeloproliferative forms of the disease which can be
conjunction with corticosteroids as a steroid-sparing agent for indi- very responsive to these drugs as discussed above. Elevated serum IgE
viduals requiring higher doses of prednisone. Some have advocated and TARC levels were associated with responsiveness to steroids in
its use as initial therapy for these disorders [99]. In the retrospective the lymphocyte-variant of HE [19].
study, 46/188 patients were treated with IFN-a (mostly in combina- Summary. Corticosteroids are first-line therapy in patients with
tion with glucocorticoids) with response rates of 50 and 75% as HE in whom a clonal population of T-cells with an abnormal immu-
monotherapy or combination therapy, respectively [19]. The optimal nophenotype are identified and other causes of an elevated eosinophil
starting or maintenance dose of IFN-a has not been well defined, but count are excluded.
the initial dose required to control eosinophil counts often exceeds
the doses needed to maintain a remission [101]. Initiation of therapy Antibody approaches for HES
at one million units by subcutaneous injection thrice weekly (tiw) Mepolizumab. Anti-IL-5 antibody approaches have been studied
and gradual escalation of the dose to 3–4 million units tiw or higher in HES based on the cytokine’s role as a differentiation, activation,
may be required to control HE in some patients. Remissions have and survival factor for eosinophils. Mepolizumab is a fully humanized
been associated with improvement in clinical symptoms and organ monoclonal IgG antibody that inhibits binding of IL-5 to the a chain
disease, including hepatosplenomegaly [95,99], cardiac and throm- of the IL-5 receptor expressed on eosinophils [117]. In HES patients,
boembolic complications [94,96], mucosal ulcers [97], and skin regression of constitutional symptoms, eosinophilic dermatologic
involvement [100]. Treatment of four HES patients with PEG-IFN-a- lesions, and improvements FEV1 measurements in individuals with
2b among a larger cohort of BCR-ABL-negative MPN cohort resulted pulmonary disease have been observed with anti-IL-5 antibody ther-
in one complete and one partial response, but side effects required apy [118–120]. Among the few patients studied, response has not
that the initial study dose be reduced from 3 to 2 mcg/kg/week [102]. been predicted by pretreatment serum IL-5 levels or presence of
A lower starting dose of 90 mcg/kg weekly (e.g., 1–1.5 mcg/kg FIP1L1-PDGFRA. Rebound eosinophilia, accompanied by increases in
weekly) is better tolerated based on the experience of PEG-IFN-a-2a serum IL-5 levels, has been noted in some cases, and tachyphylaxis
in PV and ET [103,104]. Side effects of short- and longer-acting for- has been observed with repeated doses without development of neu-
mulations of IFN-a are usually dose dependent and include fatigue tralizing antibodies [116]. In the largest study of HES patients to
date, the safety and steroid-sparing effects of mepolizumab was eval- 134] with one patient relapsing at 40 months [135]. Allogeneic trans-
uated in a randomized, double-blind, placebo-controlled trial of 85 plantation using nonmyeloablative conditioning regimens have been
FIP1L1-PDGFRA-negative patients [121]. Blood eosinophil levels were reported in three patients, with remission duration of 3–12 months at
stabilized at <1,000 cells/mm3 on 20–60 mg/day prednisone during a the time of last reported follow-up [136,137]. In one patient who
run-in period of up to 6 weeks. Patients were subsequently random- underwent an allogeneic stem cell transplantation from an HLA-
ized to intravenous mepolizumab 750 mg or placebo every 4 weeks matched sibling, the patient was disease free at 3 years, and there was
for 36 weeks. No adverse events were significantly more frequent no evidence of the FIP1L1-PDGFRA fusion which was present at
with mepolizumab compared to placebo. A significantly higher pro- diagnosis [138]. Despite success in selected cases, the role of trans-
portion of mepolizumab-treated HES patients versus placebo were plantation in HES is not well established.
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 Supportive care and surgery
follow of 78 patients treated for a mean exposure of 251 weeks (range
4–302 weeks), the median daily prednisone dose decreased from 20 Leukapheresis can elicit transient reductions in high leukocyte and
to 0 mg in the first 24 weeks, and 62% percent of patients were pred- eosinophil counts, but is not an effective maintenance therapy [139–
nisone free without other HES medications for 12 consecutive 141]. Similar to other MPNs, splenectomy has been performed for
weeks [122]. Mepolizumab is not currently approved by the FDA, but hypersplenism-related abdominal pain and splenic infarction, but is
is currently available on a compassionate use basis (ClinicalTrials.gov not considered standard treatment [20,142]. Anticoagulants and anti-
Identifier NCT00244686) for individuals with life-threatening HES platelet agents have demonstrated variable success in preventing
who have failed prior therapies. recurrent thromboembolism [20,143,144].
Reslizumab is a humanized anti-IL5 IgG4 mAb currently in clinical Advanced cardiac disease is less common today in patients with
trials for pediatric subjects with eosinophilic esophagitis and for eosinophilic disease. Cardiac surgery can extend the life of patients
patients with eosinophilic asthma, but has not yet been evaluated with late-stage heart disease manifested by endomyocardial fibrosis,
extensively in HES [123]. In a double-blind, placebo-controlled, mural thrombosis, and valvular insufficiency [18,24], Mitral and/or
randomized trial, reslizumab significantly reduced intraepithelial tricuspid valve repair or replacement [145–149] and endomyocardec-
esophageal eosinophil counts in children and adolescents with eosino- tomy for late-stage fibrotic heart disease [146,150] can improve car-
philic esophagitis, but symptom improvement was observed in both diac function. Bioprosthetic devices are generally preferred over their
treatment groups [124]. mechanical counterparts because of the reduced frequency of valve
It is unknown whether mepolizumab or other anti-IL5 antibody thrombosis.
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 䊏 Concluding Remarks
cells only develop a general myeloproliferative disease [78]. In con- A more sophisticated understanding of the cellular and molecular
trast, expression of FIP1L1-PDGFRA together with overexpression of basis of eosinophilic disorders has translated into more biologically
IL-5 mimics eosinophilic disease much better in mice with typical oriented classification schemes which carry therapeutic implications.
features of HES such as tissue infiltration of eosinophils [125]. In this regard, imatinib for has dramatically reversed the poor prog-
Alemtuzumab. Alemtuzumab is an anti-CD52 monoclonal anti- nosis of patients previously diagnosed as “HES” and who likely repre-
body that has been evaluated in idiopathic HES based on expression of sented a significant portion of older series of patients who exhibited a
the CD52 antigen on eosinophils [126,127]. Similar to mepolizumab, it poor prognosis. Corticosteroids, interferon-alpha, hydroxyurea/other
has not been formally evaluated in myeloid-related eosinophilias. In chemotherapy, and targeted antibodies can elicit clinical benefit in
patients with refractory HES, alemtuzumab administered intravenously the primary eosinophilias, but response durability is variable, and
at a dose of 5–30 mg once to thrice weekly, elicited a complete hema- treatment is often complicated by both short- and long-term side
tologic remission (CHR) in 10/12 subjects (83%), with two patients effects. Regarding future directions, the recently approved JAK1/2
achieving a partial remission. Patients with CHR who received mainte- inhibitor ruxolitinib (and other JAK inhibitors currently being eval-
nance alemtuzumab therapy exhibited significantly longer time to pro- uated in phase I-III trials of myelofibrosis) may have a role in
gression than patients who were only observed. Eleven patients patients with eosinophilic disease. For example, rare patients with HE
relapsed (only one while on maintenance), and six were rechallenged have been found to carry the JAK2 V617F activating mutation
with alemtuzumab. Five (83%) achieved second CHR after a median of [151,152]. More germane to eosinophil biology is the finding that the
3.5 weeks, for a median duration of 123 weeks [128,129]. JAK2 pathway mediates antiapoptosis signals in eosinophils in
Summary. Use of anti-IL-5 and anti-CD52 antibody approaches response to GM-CSF and IL-5 [153,154] in addition to FIP1L1-
in the treatment of HES remain investigational. Potential benefits PDGFRa [155]. Inhibition of this signaling cascade may be a useful
include resolution of eosinophilia and disease-related symptomology, therapeutic approach across eosinophilic disorders regardless of their
and a steroid-sparing effect (mepolizumab). However, with discontin- subtype. In addition, the finding that PDGF receptor fusion onco-
uation of therapy, benefits appear to be short lived and the potential genes skew proliferation and differentiation toward the eosinophil lin-
for rebound eosinophilia exists. Maintenance therapy with these anti- eage in a process that requires NF-jB suggests the possibility for new
bodies is generally required to sustain responses. treatments that target this pathway [156].
Transplantation
Bone marrow/peripheral blood stem cell allogeneic transplantation
has been attempted in patients with aggressive disease. Disease-free
䊏 Acknowledgment
survival ranging from 8 months to 5 years has been reported [130– Dr. Gotlib thanks Jenny Ma for her editorial assistance.
䊏 References syndromes. J Allergy Clin Immunol 2012;130:

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

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Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or

Division of Hematology, Stanford Cancer Center, Stanford, California

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TABLE II. 2008 World Health Organization Classification of Eosinophilic Disorders

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

䊏 References syndromes. J Allergy Clin Immunol 2012;130:

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