Received: 2 August 2017 | Accepted: 3 August 2017 DOI: 10.1002/ajh.24880

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL AJH

MALIGNANCIES

World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management

Jason Gotlib

Stanford Cancer Institute, Stanford, California 94305-5821 Abstract Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or Correspondence Jason Gotlib, Stanford Cancer Institute, 875 reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Blake Wilbur Drive, Room 2324, Stanford, Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count CA 94305-5821. 3 Email: [email protected] greater than 1500/mm and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridiza- tion, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.

Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evalu- ation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi- molecular classification scheme of disease subtypes which includes the major category “myeloid/ lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB,orFGFR1 or with PCM1-JAK2,” and the “MPN subtype, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosino- phila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.

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

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

Am J Hematol. 2017;92:1243–1259. wileyonlinelibrary.com/journal/ajh VC 2017 Wiley Periodicals, Inc. | 1243 1244 | AJH GOTLIB ET AL. occurs in approximately 10% or less of patients with idiopathic identified, the pool of patients with classically defined idiopathic HES hypereosinophilia.3–5 Although usually diagnosed between the ages of has diminished. HES can be considered a provisional diagnosis until a 20 and 50, idiopathic hypereosinophilia or CEL may arise at the primary or secondary cause of eosinophilia is ascertained. extremes of age, with infrequent cases being described in infants and In 2011, the Working Conference on Eosinophil Disorders and Syn- children.6–8 In the SEER database of 131 incident cases between 2001 dromes proposed a new terminology for eosinophilic syndromes.18 The and 2005, the male-to-female ratio was 1.47, and rates increased with panel recommended the higher-level term “Hypereosinophilia (HE)” for age to a peak between 65 and 74 years.1 For reasons that are persistent and marked eosinophilia (AEC > 1500/mm3). In turn, HE sub- unknown, the overwhelming majority of patients with FIP1L1-PDGFRA types were divided into a hereditary (familial) variant (HEFA), HE of unde- 3,9,10 or myeloproliferative variants of HES are male, whereas other termined significance (HEUS), primary (clonal/neoplastic) HE produced by eosinophilia subtypes exhibit no clear gender bias. clonal/neoplastic eosinophils (HEN), and secondary (reactive) HE (HER).

HEUS wasintroducedasanovelterminlieuof“idiopathic hypereosino- 1.2 | Definition of eosinophilia and classification philia.” Any HE (not just idiopathic) associated with organ damage is referred to as “HES” with specific variants designated by subscripts (e.g., The upper limit of normal for the range of % eosinophils in the periph- HESUS,HESN,andHESR). Additional recommendations advanced by the eral blood is 3%-5% with a corresponding absolute eosinophil count consensus panel are summarized in their report. (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 1.3 | Clinical presentation and diagnosis 1500/mm3), moderate (AEC 1500–5000/mm3) and severe (AEC >5000/mm3).11–13 The varied clinical presentations of primary eosinophilias/HES reflect The classification of eosinophilic diseases was revised in the 2008 their heterogeneous pathophysiology. In two retrospective series pub- World Health Organization scheme of myeloid neoplasms and reaf- lished in 1982 and 2009, eosinophilia was an incidental finding in 12% firmed in 2016 (Table 1).14,15 In recognition of the growing list of recur- and 6% of patients, respectively.19,20 The most common presenting rent, molecularly-defined primary eosinophilias resulting from fusion signs and symptoms were weakness and fatigue (26%), cough (24%), tyrosine kinase genes, the major category “Myeloid/lymphoid neo- dyspnea (16%), myalgias or angioedema (14%), rash or fever (12%), and plasms with eosinophilia and rearrangement of PDGFRA, PDGFRB,or rhinitis (10%).21 In HES, leukocytosis (e.g., 20,000–30,000/mm3 or FGFR1 or with PCM1-JAK2” has been defined, with the latter fusion, higher) with peripheral eosinophilia in the range of 30%-70% is a com- PCM1-JAK2, added as a provisional entity in 2016.15 Within the major mon finding17,19–22; the aforementioned retrospective analysis of 188 WHO category of myeloproliferative neoplasms (MPNs), “chronic patients from 2009 observed a mean peak eosinophil count of 6600/ eosinophilic leukemia-not otherwise specified” (CEL-NOS) is one of mm3 with a range of 1500–400,000/mm3.20 Other hematologic find- seven disease entities within this group (Table 1).16 CEL-NOS is ings include peripheral blood or bone marrow neutrophilia, basophilia, defined by absence of the Philadelphia chromosome or a rearrange- myeloid immaturity, and both mature and immature eosinophils with ment involving PDGFRA/B and FGFR1, and the exclusion of other acute varying degrees of dysplasia.22–24 In one series, anemia was present in or chronic primary marrow neoplasms associated with eosinophilia 53% of patients, thrombocytopenia was more common than thrombo- such as acute myeloid leukemia (AML), myelodysplastic syndrome cytosis (31% vs. 16%), and bone marrow eosinophilia ranged from 7– (MDS), systemic mastocytosis (SM), the classic MPNs (chronic myeloid 57% (mean 33%).24 Marrow findings of Charcot-Leyden crystals, and in leukemia, polycythemia vera, essential thrombocythemia, and primary some cases, increased blasts and marrow fibrosis, are also observed.24 myelofibrosis), and MDS/MPN overlap disorders (e.g., chronic myelo- Essentially all organ systems may be susceptible to the effects of monocytic leukemia, CMML) (Table 2). CEL-NOS is morphologically sustained eosinophilia [reviewed in 25]. During follow-up of patients characterized by an increase in blasts in the bone marrow or blood (but with hypereosinophilia, dermatologic involvement was the most com- fewer than 20% to exclude acute leukemia as a diagnosis), and/or there mon clinical manifestation reported in 69% of patients, followed by is evidence for a clonal marker.16 A diagnosis of idiopathic HES pulmonary (44%) and gastrointestinal (38%) manifestations. Cardiac requires exclusion of all primary and secondary causes of hyerpeosino- disease unrelated to hypertension, atherosclerosis or rheumatic disease philia as well as lymphocyte-variant hypereosinophilia (Table 2). The was eventually identified in 20% of patients (only 6% at the time of ini- modern definition of HES is a vestige of the historical criteria outlined tial presentation).20 Progressive heart failure is a proto-typical example by Chusid and colleagues in 1975: the absolute eosinophil count of eosinophil-mediated organ injury. It involves a multi-step pathophys- is > 1500/mm3 for more than 6 months, and tissue damage is pres- iological process involving eosinophil infiltration of cardiac tissue and ent.17 The requirement that eosinophilia persist for more than 6 release of toxic mediators from eosinophils [reviewed in 19, 25]. Endo- months is less consistently embraced today because of the availability cardial damage with resulting platelet thrombus can lead to mural of more sophisticated tools to rapidly evaluate eosinophilia and the thrombi and increased embolic risk. In the later fibrotic stage, fibrous need for some patients to receive expedited treatment to minimize thickening of the endocardial lining can evolve to a restrictive cardio- organ damage. In contrast to “HES,”“idiopathic hypereosinophilia” is myopathy.19,25 Valvular insufficiency results from mural endocardial the preferred term when end-organ damage is absent.16 Because of thrombosis and fibrosis involving leaflets of the mitral or tricuspid the increasing proportion of cases in which a clonal marker can be valves.26–28 GOTLIB ET AL. AJH | 1245

TABLE 1 Revised 2016 World Health Organization (WHO) classification of myeloid neoplasms

1. Acute myeloid leukemia and related neoplasms

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

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

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

5. Mastocytosis

6. Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB,orFGFR1, or with PCM1-JAK2 · Myeloid/lymphoid neoplasms with PDGFRA rearrangement · Myeloid neoplasms with PDGFRB rearrangement · Myeloid/lymphoid neoplasms with FGFR1 abnormalities · Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

2 | DIAGNOSIS lymphoma,33 and acute lymphoblastic leukemias.34 Rare conditions associated with eosinophilia include familial eosinophilia whose genetic 2.1 | Step 1: Exclude secondary (reactive) causes of basis remains unknown, hyper IgE Syndrome, Omenn Syndrome, epi- eosinophilia sodic angioedema and eosinophilia (Gleich’ssyndrome),and eosinophilia-myalgia syndrome (e.g., possibly related to tryptophan Secondary eosinophilia has numerous causes that may require diagnos- ingestion, or of historical interest, the epidemic of toxic-oil syn- tic evaluation by a cadre of different sub-specialty consultants. In drome).18 Repeated ova and parasite testing, stool culture, and anti- developing countries, eosinophilia most commonly derives from infec- body testing for specific parasites (e.g., strongyloides) is paramount for tions, particularly tissue-invasive parasites.13 Allergy/atopy and hyper- identifying infectious etiologies in the appropriate clinical context. sensitivity conditions, drug reaction, collagen-vascular disease (e.g., Additional laboratory and imaging tests (e.g., chest-x-ray, electrocardio- Churg-Strauss Syndrome, granulomatosis with polyangiitis [Wegener’s], gram and echocardiography, CT scan of the chest, abdomen/pelvis) are systemic lupus erythematosus), pulmonary eosinophilic diseases (e.g., guided by the patient’s travel history, presenting symptoms, and find- idiopathic acute or chronic eosinophilia pneumonia, tropical pulmonary ings on physical examination. For eosinophilic lung diseases, pulmonary eosinophilia, allergic bronchopulmonary aspergillosis, etc), allergic gas- function testing, bronchoscopy, serologic tests (e.g., aspergillus IgE to troenteritis (with associated peripheral eosinophilia), and metabolic evaluate for allergic bronchopulmonary aspergillosis [ABPA]) may be conditions such as adrenal insufficiency are diagnostic considerations obtained to further characterize lung involvement. in the appropriate clinical context.29–31 Nonmyeloid malignancies may be associated with secondary eosinophilia which results from the pro- 2.2 | Step 2: Evaluate for primary (clonal) eosinophilia duction of cytokines such as IL-3, IL-5, and GM-CSF which promote eosinophil differentiation and survival. For example, these cytokines If secondary causes of eosinophilia are excluded, the work-up should may be elaborated from malignant cells in T-cell lymphomas,32 Hodgkin proceed to the evaluation of a primary bone marrow disorder. 1246 | AJH GOTLIB ET AL.

TABLE 2 Revised 2016 World Health Organization Classification of Eosinophilic Disorders41

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

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

A myeloid or lymphoid neoplasm, usually with prominent eosinophilia

and

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

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

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

and

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

Diagnostic criteria of MPN or acute leukemia associated with FGFR1 rearrangement

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

or

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

and

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

Diagnostic criteria for myeloid/lymphoid neoplasms with PCM1-JAK2

A myeloid or lymphoid neoplasm, often with prominent eosinophilia

and

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

CEL, NOS

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

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

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

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

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

Idiopathic HES

Exclusion of the following:

Reactive eosinophilia

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

CEL, NOS

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

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

The absolute eosinophil count of >1.5X109/L must persist for at least 6 mo, and tissue damage must be present. If there is no tissue damage, idiopathic HES is the preferred diagnosis. aPatients presenting with myeloproliferative neoplasm, AML, or lymphoblastic leukemia/lymphoma with eosinophilia and a FIP1L1-PDGFRA fusion gene are also assigned to this category. blf appropriate molecular analysis is not available, this diagnosis should be suspected if there is a Ph-chromosome-negative MPN with the hematologic features of chronic eosinophilic leukemia associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase, and increased BM mast cells. cCases with fusion genes typically associated only with BCR-ABL1-like B-lineage ALL are specifically excluded. dBecause t(5;12)(q31q33;p12) does not always lead to an ETV6-PDGFRB fusion gene, molecular confirmation is highly desirable. If molecular analysis is not available, this diagnosis should be suspected if there is a Ph-chromosome-negative MPN associated with eosinophilia and with a translocation with a 5q3133 breakpoint. eOther variants giving rise to a fusion gene between JAK2 and an alternative partner include ETV6-JAK2 [t(9; 12)(p24.1;p13.2)] or BCR-JAK2 [t(9;22) (p24.1;q11.2)]. GOTLIB ET AL. AJH | 1247

Examination of the blood smear and blood tests (e.g., circulating blasts, similarly rare.14 In these cases, the association of t(8p11–12) break- dysplastic cells, monocytosis, elevated serum B12 or tryptase level) in point with lymphoblastic lymphoma with eosinophilia and myeloid conjunction with bone marrow morphologic, cytogenetic, and immuno- hyperplasia was first described in 1995, and was previously referred to phenoytpic analysis will help ascertain whether the differential diagno- as “8p11 myeloproliferative syndrome” or “stem cell leukemia/lym- sis of eosinophilia includes a well-defined WHO myeloid neoplasm phoma.” Following the discovery of the ZNF198-FGFR1 fusion gene in – such as systemic mastocytosis, chronic myeloid leukemia, acute mye- 1998 by several groups,42 45 some 14 fusion partners of FGFR1 have loid leukemia (especially the historically-defined M2 and M4 Eo been reported.41 The PCM1-JAK2 fusion was added to this WHO French-American-British subtypes), myelodysplastic syndrome (MDS), major category as a provisional entity. Fusion tyrosine kinases involving or MDS/MPN overlap disorder (e.g., CMML). Although not formally FLT3 (most commonly the ETV6-FLT3 fusion) typically present as an included in the WHO monograph, the term “myeloproliferative variant MPN and/or T-cell acute lymphoblastic leukemia/lymphoma with 46 41 of hypereosinophilia” has been used to refer to some of these marrow- eosinophilia, but have not yet been formally added to this category. derived eosinophilic myeloid malignancies because of clinicopathologic JAK2 and FLT3 rearrangements can be surmised by reciprocal translo- similarity to CML and the BCR-ABL1-negative MPNs.9,25 cations involving the 9p24 and 13q12 breakpoints, respectively. Laboratory evaluation of primary eosinophilia should begin with A negative screen for PDGFRA/B-orFGFR1-rearranged eosino- screening of the peripheral blood for the FIP1L1-PDGFRA gene fusion philias should prompt consideration of a diagnosis of CEL-NOS when (by RT-PCR or interphase/metaphase FISH) (Figure 1). FISH probes there is cytogenetic and/or morphologic evidence of an eosinophilic 15 that hybridize to the region between the FIP1L1 and PDGFRA genes myeloid malignancy that is otherwise not classifiable. CEL- NOS may are used to detect the presence of the cytogenetically occult 800-kb be distinguished from HES by the presence of a nonspecific clonal > deletion on 4q12 that results in FIP1L1-PDGFRA.9,35 Since the CHIC2 cytogenetic abnormality or increased blast cells ( 2% in the peripheral > < gene is located in this deleted genetic segment, this widely available blood or 5% in the bone marrow, but 20% blasts in both compart- clinical test is referred to as “FISH for the CHIC2 deletion”.35 In instan- ments). The marrow morphology of patients with CEL-NOS can be dis- ces where FIP1L1-PDGFRA screening is not available, evaluation of the tinguished from patients with HES, and is correlated with a higher serum tryptase can be a useful surrogate marker for FIP1L1-PDGFRA- frequency of abnormal karyotypes, myeloid mutations, and shortened 47 positive disease since increased levels segregate with this molecular survival compared to the latter group. abnormality and myeloproliferative variants of hypereosinophilia.36 Lymphocyte-variant hypereosinophilia is a more obscure diagnos- FIP1L1-PDGFRA has also been also identified in cases where bone mar- tic entity characterized by an abnormal T-cell population (demonstrated rows show increased mast cell numbers with associated peripheral by peripheral blood lymphocyte immunophenotyping or T cell receptor 4 gene rearrangement studies) which may be associated with excessive eosinophilia. The bone marrows of such patients typically exhibit loose eosinophilopoietic cytokine production in vitro (e.g., serum interleukin- mast cell clusters compared to classic SM with dense mast cell aggre- 5).16,48,49 If none of the aforementioned conditions is identified, a diag- gates associated with the KIT D816V mutation.4 In both disease sub- nosis of HES is made if organ damage is present, and a diagnosis of idi- types, mast cells stain for tryptase, CD117, and CD25, and the opathic hypereosinophilia is rendered if organ compromise is not marrows frequently exhibit increased fibrosis.37 The FIP1L1-PDGFRA found. With the availability of next-generation sequencing panels, iden- fusion has also been found in cases of AML and T-cell lymphoblastic tification of additional mutations in cases of idiopathic hypereosino- lymphoma associated with eosinophilia.38 In addition to dysregulation philia/HES is expected to be more commonplace. For example, among of PDGFRA by fusion to FIP1L1 or other partner genes, activating point 426 patients in the German Registry with hypereosinophilia of mutations have been identified in PDGFRA in patients with hypereosi- unknown significance, KIT D816V and JAK2 V617F mutations were nophilia.39 Although there was variability in their transforming ability, identified in 3% and 4% of patients, respectively.50 Another study injection of cells harboring these mutants into mice induced a found myeloid mutations in 14/51 patients with a diagnosis of HES, leukemia-like disease. Imatinib treatment significantly decreased leuke- including a single mutated gene in 7 patients and 2 or more mutated mic growth and prolonged survival.39 genes in another 7 patients. The most commonly mutated genes were: Absence of the FIP1L1-PDGFRA fusion should prompt evaluation ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and for other primary eosinophilias associated with recurrent molecular NOTCH1 (14%). Patients with HES ultimately found to have positive abnormalities. Molecular evidence for a PDGFRA, PDGFRB,orFGFR1 sequencing results exhibited a prognosis that was inferior to HES fusion gene is often accompanied by its abnormal karyotype equiva- patients without mutation findings, but similar to patients with CEL- lent: rearrangement of 4q12 (PDGFRA fusion partners besides FIP1L1), NOS.51 5q31–33 (PDGFRB)or8p11–12 (FGFR1).14 Despite the rare frequency (<1%) of PDGFRB-rearrangements in cytogenetically-defined cases of 2.3 | Lymphocyte-variant hypereosinophilia CMML and other myeloid neoplasms (e.g., atypical CML, juvenile myelomonocytic leukemia, MDS/MPN overlap disorders),40 their iden- Some patients may exhibit expansion of a cytokine-producing, immu- tification is critical given their responsiveness to imatinib. Over 30 nophenotypically-aberrant T-cell population.16,49 The condition is a gene fusion partners of PDGFRB have been described.41 Eosinophilic mixture of clonal and reactive processes: it is clonal with regard to the myeloid neoplasms related to fusions involving the FGFR1 gene are production of abnormal T-cell lymphocytes; however, the eosinophilia 1248 | AJH GOTLIB ET AL.

FIGURE 1 Diagnostic and Treatment Algorithm Based on Revised 2016 WHO Classification of Eosinophilic Disorders [Color figure can be viewed at wileyonlinelibrary.com] is reactive to the eosinophilopoietic growth factors elaborated by the T- elevated CD5 expression on CD3-CD41 cells, and loss of surface CD7 cells. The immunophenotype of these lymphocytes include double- and/or expression of CD27.49 These patients typically have cutaneous negative, immature T-cells (e.g., CD31CD4-CD8-)orabsenceofCD3 signs and symptoms as the primary disease manifestation. However, a (e.g., CD3-CD41), a normal component of the T-cell receptor recent series of 21 patients with a CD3-CD41 T-cell phenotype showed complex.52–54 Additional immunophenotypic abnormalities include that involvement of additional organ systems was prevalent, including GOTLIB ET AL. AJH | 1249 superficial adenopathy (62%), rheumatologic (29%), gastrointestinal hypereosinophilia,63 a multivariate analysis revealed that age >60 years, (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%).55 hemoglobin < 10 g/dL, cardiac involvement, and hepatosplenomegaly In patients with T-cell mediated hypereosinophilia with elevated were associated with inferior overall survival. Eleven patients (11%) har- IgE levels, lymphocyte production of IL-5, and in some cases IL-4 and bored a pathogenetic mutation in one of the following genes: TET2, IL-13, suggests that these T-cells have a helper type 2 (Th2) cytokine ASXL1, KIT, IDH2, JAK2, SF3B1,andTP53, but the presence of one of profile.49,52–54,56,57 In a study of 60 patients primarily from dermatol- the mutations was only significant in a univariate analysis of survival. ogy clinics, 16 demonstrated circulating T-cells with an abnormal The prognosis of WHO-defined CEL-NOS is poor. In a recently immunophenotype.48 Clonal rearrangement of T-cell receptor genes reported cohort of 10 patients, the median survival was 22.2 months, was demonstrated in half of these individuals (8/60 total patients). The and 5 of the 10 patients developed acute transformation after median abnormal T-cells secreted high levels of interleukin-5 in vitro, and dis- of 20 months from diagnosis.64 Three of 5 patients who did not played an activated immunophenotype (e.g., CD25 and/or HLA-DR develop AML died with active disease; one patient underwent an allo- expression). A case of lymphocyte-variant hypereosinophilia was geneic stem-cell transplant and maintained a long-term remission, and reported in a patient with chronic active Epstein-Barr virus infection the remaining patient achieved a complete remission on imatinib and 64 and an EBV-infected T-cell clone producing eosinophilopoietic cyto- hydroxyurea. kines. Slightly elevated EBV DNA levels were detected in 2 of an addi- In the lymphocyte-variant of hypereosinophilia, an indolent disease tional 15 lymphocyte-variant hypereosinophilia patients tested, but the course is usually observed. However, patients may infrequently causal relationship EBV and this subtype of eosinophilia is unclear.58 develop either T-cell lymphoma or Sezary syndrome, indicating this 49,55 Consensus criteria for the diagnosis of lymphocyte-variant hyper- condition has malignant potential. Accumulation of cytogenetic eosinophilia have not been established. The finding of isolated T-cell changes (e.g., partial 6q and 10p deletions, trisomy 7) in T-cells, and - 1 clonality by PCR without T-cell immunophenotypic abnormalities or proliferation of lymphocytes with the CD3 CD4 phenotype have 57,65–67 demonstration of Th2 cytokine production is not felt to be sufficient to been observed with progression to lymphoma. make a diagnosis of this eosinophilia variant.59 Despite a recent study In WHO-defined myeloid malignancies, the prognostic importance demonstrating that a high proportion of idiopathic HES patients exhibit of associated eosinophilia has been only been studied in few diseases. a clonal T-cell receptor gene rearrangement by PCR (18/42 patients, In a series of 123 patients with systemic mastocytosis, eosinophilia 43%), it is unclear whether such clonal T-cell populations are always was prevalent in 34% of cases, but was prognostically neutral and not 68 relevant to the disease process.60 Detection of elevated serum levels affected by exclusion of FIP1L1-PDGFRA-positive cases. In a study of of TARC, a chemokine implicated in Th2-mediated diseases, in addition 1008 patients with de novo MDS, eosinophilia (and basophilia) pre- to the finding of increased in vitro production of cytokines from cul- dicted a significantly reduced survival without having a significant 69 tured peripheral blood mononuclear cells and/or T-cells (research- impact on leukemia-free survival. A retrospective of 288 individuals based assays), may provide additional support for a diagnosis of with newly diagnosed MDS revealed that significantly higher numbers lymphocyte-variant hypereosinophilia.20,59,61 of patients with eosinophilia or basophilia (compared to patients with neither) had chromosomal abnormalities carrying an intermediate or 70 3 | RISK STRATIFICATION poor prognosis. In addition, the overall survival rate was significantly lower, and evolution to AML occurred more frequently.

Older case series indicate that lives of patients with HES were over- | shadowed by early cardiac death. A review of 57 HES cases published 4 RISK-ADAPTED THERAPY through 1973 reported a median survival of 9 months and the 3-year | survival was only 12%.17 Patients usually presented with advanced dis- 4.1 General considerations ease, with congestive heart failure accounting for 65% of deaths at It is difficult to predict what duration and severity of eosinophilia will autopsy. In addition to cardiac disease, peripheral blood blasts or a precipitate tissue damage in individual patients. Inadequate data exists 3 16 WBC count greater than 100,000/mm were poor prognostic factors. to support initiation of therapy based on a specific eosinophil count in A later report of 40 HES patients cited a 5-year survival rate of 80%, the absence of organ disease, although an absolute eosinophil count of decreasing to 42% at 15 years.23 Factors predictive of a worse outcome 1500–2000/mm3 has been recommended by some as a threshold for included the presence of a concurrent myeloproliferative syndrome, starting treatment.71 Treatment algorithms have incorporated serial corticosteroid-refractory hypereosinophilia, cardiac disease, male sex, monitoring of eosinophil counts, bone marrow aspiration and biopsy and the height of eosinophilia.23 A recent retrospective review of 247 with cytogenetics, evaluation of clonality (e.g., T-cell receptor gene HES patients at the Mayo Clinic identified 23 subjects who died during rearrangement, immunophenotyping), and directed organ assessment the 19 years of the review period. The cause of death was identified in (e,g. echocardiography, pulmonary function testing) in order to identify 15 (65%) patients, including the following etiologies: cardiac dysfunc- occult organ disease and defined causes of eosinophilia which may tion (33%), infection (20%), unrelated malignancy (20%), thrombo- emerge after an initial diagnosis of HES.21,72 embolic phenomena (13%), and vascular disease (13%).62 In a recent Given the historically poor-prognosis of chronic eosinophilic leuke- Mayo Clinic report of 98 patients with HES and idiopathic mias and HES, and the exquisite sensitivity to imatinib in patients with 1250 | AJH GOTLIB ET AL. rearranged PDGFRA/B, consensus has emerged that these individuals optimal imatinib dose which sustains a molecular remission has not be treated in the absence of organ dysfunction. Proactive treatment been defined. has the potential to not only forestall tissue damage, but also to The natural history of imatinib-treated FIP1L1-PDGFRA-positive achieve complete molecular remissions. myeloid neoplasms was evaluated in an Italian prospective cohort of In patients with eosinophilia-related organ damage (e.g., heart, 27 patients with a median follow-up period of 25 months (range 15– lungs, gastrointestinal, central nervous system, skin), risk-adapted ther- 60 months).10 Patients were dose escalated from an initial dose of apy rests on the premise of identifying the specific WHO-defined 100 mg daily to a final dose of 400 mg daily. Complete hematologic eosinophilic disorder and individualizing treatment accordingly. For remission was achieved in all patients within 1 month, and all patients patients with an eosinophilia-associated WHO-defined myeloid malig- became PCR negative for FIP1L1-PDGFRA after a median of 3 months nancy (e.g., AML, MDS, systemic mastocytosis, CML other MPNs, and of treatment (range 1 to 10 months). Patients continuing imatinib MDS/MPN), therapy is dictated by disease-specific algorithms and remained PCR-negative during a median follow-up period of 19 guidelines. As a multikinase inhibitor, imatinib has not only demon- months (range 6–561 months). Another European study prospectively strated remarkable benefit in CML, but is now definitive first line ther- assessed the natural history of molecular responses to imatinib doses apy in patients with FIP1L1-PDGFRA-positive disease, and the rare of 100–400 mg daily.3 Among 11 patients with high pretreatment tran- patients with alternate PDGFRA fusions or rearranged PDGFRB.The script levels, all achieved a 3-log reduction in transcript levels by one discussion of treatment options below will focus on the experience year of therapy, and 9 of 11 patients achieved a molecular remission. with imatinib in PDGFRA/B-rearranged neoplasms and separately the In a long-term follow-up analysis of the Mayo cohort of 18 imatinib- therapeutic options available for patients with CEL, NOS, HES, and treated FIP1L1-PDGFRA-positive patients, 1 patient with accelerated lymphocyte-variant hypereosinophilia, which is based primarily on small disease at presentation transformed to AML, but the median survival case series and retrospective studies. The use of other chemotherapeu- of the entire cohort was not reached and the otherwise excellent clini- tics for HES, and recent investigational approaches with antibodies, will cal outcomes corroborated the findings of other studies.80 also be addressed. Although in-depth and durable molecular responses occur with imatinib, discontinuation of the drug can lead to relapse.3,10 In a dose 4.2 | PDGFRA/B-rearranged neoplasms: The imatinib de-escalation trial of imatinib in 5 patients who had achieved a stable experience hematologic and molecular remission at 300–400 mg daily for at least one year, molecular relapse was observed in all patients after 2–5 The success of imatinib in CML led to its empiric use in patients with months of either dose imatinib reduction or discontinuation.81 Molecu- hypereosinophilia who exhibited signs suggestive of a myeloprolifera- lar remissions could be re-established with re-induction of imatinib in tive disorder. Several case reports and small case series of HES patients – were published in 2001–2002 highlighting rapid and complete hemato- all cases at a dose range of 100 400 mg daily. Hematologic relapse logic responses to imatinib 100–400 mg daily.73–75 FIP1L1-PDGFRa was noted only several weeks after discontinuation of imatinib in 4 5 was ultimately identified as the therapeutic target of imatinib.9,76 The patients in a Mayo series. In the French series, imatinib was stopped identification of the clonal marker FIP1L1-PDGFRA in these cases in 11 patients; 6 of the patients subsequently relapsed, but 5 remained – operationally re-defined them as a form of chronic eosinophilic leuke- in persistent complete hematologic or molecular remission (range, 9 79 mia, and now comprise the WHO major category of “myeloid and 88 months). In two patients with undetectable FIP1L1-PDGFRA tran- lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, scripts by PCR for four years, no evidence of disease was detected for 82 PDGFRB,orFGFR1, or PCM1-JAK2.”14 more than two years after discontinuation of imatinib. In sum, these The hematologic benefit of imatinib in FIP1L1-PDGFRA-positive data indicate that imatinib can effectively suppress, but not eliminate myeloid neoplasms has been confirmed in numerous studies. Molecular the FIP1L1-PDGFRA clone in most patients, although some may experi- remissions were first reported by the NIH group by PCR testing of the ence prolonged molecular remissions after stoppage of imatinib. peripheral blood in 5 of 6 FIP1L1-PDGFRA-positive patients after 1–12 Ongoing treatment is generally recommended similar to CML guide- months of imatinib therapy.77 Several reports have now described lines, and the role of imatinib discontinuation requires further evalua- rapid induction of molecular remission in imatinib-treated FIP1L1- tion in the context of clinical trials. PDGFRA positive patients or with bone marrow transplantation. In contrast to CML, very few cases of acquired imatinib resistance Although 100 mg daily may be sufficient to achieve a molecular remis- have been reported with more than 10 years of experience in treating – sion in some patients, others may require higher maintenance doses in FIP1L1-PDGFRA-positive disease.9,83 85 Most of the cases have involve the range of 300–400 mg daily. Maintenance dosing of 100–200 mg the T674I mutation within the ATP-binding domain of PDGFRa and weekly may be sufficient to achieve a molecular remission in some have occurred during the blast of disease. The T674I mutation is analo- patients.78 In a French Eosinophil Network series, a complete hemato- gous to the T315I BCR-ABL mutation in CMLthat confers resistance to logic response (CHR) was achieved in all patients, and complete molec- the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib.86 One ular response (CMR) in 95% of patients (average starting imatinib dose, patient with the FIP1L1-PDGFRA T674I mutation in blast crisis 165 mg/d). For 29 patients, imatinib was tapered to a maintenance responded briefly to sorafenib, but was followed by rapid emergence dose of 58 mg/day, permitting CHR and CMR to be sustained.79 The of a pan-resistant FIP1L1-PDGFRA D842V mutant.85 Despite in vitro GOTLIB ET AL. AJH | 1251 nanomolar activity of sorafenib, midostaurin (PKC412), or nilotinib against the T674I mutant,87–90 these drugs have limited clinical activ- ity.91 Thus far, the only report of primary resistance to imatinib relates to the tandem PDGFRA mutations, S601P and L629P, identified in a FIP1L1-PDGFRA-positive patient in the chronic phase of the disease.92 Similar to recent in vitro findings with a F604S mutation within FIP1L1- PDGFRA, the L629P mutation may induce drug resistance to imatinib by increasing stability of the fusion oncoprotein rather than interfering with drug binding.93 In patients with rearrangements of PDGFRB or PDGFRA variants other than FIP1L1-PDGFRA, case reports and series indicate that imati- nib, usually given at doses of 400 mg daily, can elicit durable hemato- logic and cytogenetic remissions [reviewed in 2; 94]. Similar to FIP1L1- PDGFRA, FISH can be used to assess response to imatinib in PDGFRB- rearranged cases (Figure 2). Long-term follow-up (median 10.2 years) of PDGFRB-rearranged patients treated with imatinib for a median duration of 6.6 years showed a 96% response rate and a 10-year over- all survival rate of 90%. None of the patients who achieved a complete cytogenetic (n 5 13) or molecular (n 5 8) remission lost their response or exhibited progression to blast crisis.95 In the blast phase of PDGFRA or PDGFRB-rearranged disease, ima- tinib can still be effective. In a case series of 17 patients blast phase or sarcoma, 15 patients treated with imatinib monotherapy, achieved durable complete hematologic and molecular remissions. Only 2 (12%) of 17 patients died after a median observation time of 65 months (range, 7–106).96 The natural history of patients with myeloid/lymphoid disease with rearranged FGFR1 follows an aggressive course usually terminat- ing in AML in 1–2 years.14 Therefore, intensive chemotherapy with regimens such as hyper-CVAD (directed to treatment of T- or B-cell lymphoma), followed by early allogeneic transplantation, is recom- FIGURE 2 Interphase FISH results using a break-apart FISH probe mended. The data for use of small molecule inhibitors for patients with for the PDGFRB gene region in a patient with MDS/MPN with – FGFR1-rearranged disease is sparse. The small molecule midostaurin eosinophilia and an abnormal karyotype, t(5;12)(q31 33;p13). (A) Representative interphase nucleus demonstrating a typical abnor- (PKC412) inhibited the constitutively activated ZNF198-FGFR1 fusion mal signal pattern of a split red and green signal (corresponding to in vitro, as well as in a patient who exhibited a hematologic (but not the PDGFRB gene disruption; see arrows) and one intact red/green 97 cytogenetic) response. Ponatinib has activity against the FGFR1 tyro- fusion signal (corresponding to the normal/intact PDGFRB allele). sine kinase98,99 and was recently shown to be active in a patient with Eighty five percent of nuclei were abnormal. (B) After 3 months of BCR-FGFR1-positive trilineage T/B/myeloid mixed phenotype acute treatment with imatinib and normalization of blood counts, a repre- sentative interphase nucleus demonstrates a normal FISH signal leukemia where it produced marked reduction of bulky lymphadenopa- pattern with two intact Red/Green fusion signals, indicating two 100 thy unresponsive to induction chemotherapy. When re-introduced intact copies of the PDGFRB gene region. All cells demonstrated a after allogeneic transplantation, it elicited a substantial reduction of normal FISH pattern. Courtesy of Dr. Rhett P. Ketterling, Mayo molecular minimal residual disease. However, the German group found Clinic, Rochester either no evidence for sustained hematologic or cytogenetic responses or progressive disease with either ponatinib or intensive chemotherapy kinases, respectively. For example, two reports highlighted complete in 7 FGFR1-rearranged patients. Four of these patients underwent allo- hematologic remissions and cytogenetic responses (1 compete and 1 geneic HSCT and were reported in CMR and alive after a median time major) in 2 patients with chronic eosinophilic leukemia with the PCM1- of 19 months (range, 8–36 months) after diagnosis and 13 months JAK2 fusion [t(8;9)(p22;p24)] treated with the JAK1/JAK2 inhibitor rux- (range, 4–29 months) after allogeneic HSCT.101 Selective and potent olitinib.102,103 Hematologic and cytognetic remissions, however, can be inhibitors of FGFR1 are in development that may offer benefit for this variable JAK2-rearranged patients, with some lasting only 1–2 years, patient group. and HSCT should be therefore considered for suitable candi- The use of small molecule inhibitors (e.g., against JAK2 and FLT3) dates.104,105 Similarly, in FLT3-rearranged cases, hematologic and cyto- should be entertained for patients with JAK2 and FLT3 fusion tyrosine genetic responses are observed with FLT3/multikinase inhibitors such 1252 | AJH GOTLIB ET AL. as sorafenib or sunitinib, but durability can be brief, necessitating con- achieved a complete or partial response.19 When hydroxyurea was sideration of HSCT.106,107 combined with corticosteroids, the overall response rate was 69%. Imatinib’s safety profile in eosinophilic disorders parallels the drug’s Interferon-a (IFN-a) can produce hematologic and cytogenetic good tolerability in CML. A few cases of cardiogenic shock have been remissions in HES and CEL patients refractory to other therapies – reported in FIP1L1-PDGFRA-positive patients after initiation of imati- including prednisone and/or hydroxyurea,112 118 or can be used in con- nib.108,109 Currently, prophylactic use of steroids during the first 7–10 junction with corticosteroids as a steroid-sparing agent for individuals days of imatinib treatment is recommended for patients with known requiring higher doses of prednisone. Some have advocated its use as 98 cardiac disease and/or elevated serum troponin levels which may be initial therapy for these disorders. In the retrospective study, 46/188 related to eosinophil-mediated heart damage or other cardiac co- patients were treated with IFN-a (mostly in combination with glucocor- morbidities.109 ticoids) with response rates of 50% and 75% as monotherapy or com- bination therapy, respectively.19 The optimal starting or maintenance 4.2.1 | Summary dose of IFN-a has not been well-defined, but the initial dose required Imatinib is considered definitive treatment for PDGFRA/B-re-arranged to control eosinophil counts often exceeds the doses needed to main- 119 neoplasms with eosinophilia. The FDA-recommended starting dose for tain a remission. Initiation of therapy at 1 million units by subcutane- patients with the FIP1L1-PDGFRA rearrangement is 100 mg daily. ous injection three times weekly (tiw) and gradual escalation of the – Cumulative data with long-term follow-up indicate that this dose is suf- dose to 3 4 million units tiw or higher may be required to control hypereosinophilia in some patients. Remissions have been associated ficient to elicit complete and durable hematologic and complete molec- with improvement in clinical symptoms and organ disease, including ular remissions. For patients with myeloid neoplasms (usually MDS/ hepatosplenomegaly,113,117 cardiac and thromboembolic complica- MPNs) with eosinophilia and rearranged PDGFRB, the recommended tions,93,95 mucosal ulcers,115 and skin involvement.118 Treatment of dose is 400 mg daily which reflects the dose consistently used in sev- four HES patients with PEG-IFN-a-2b among a larger cohort of BCR- eral case series with excellent outcomes. ABL1-negative MPN cohort resulted in 1 complete and 1 partial response, but side effects required that the initial study dose be | 4.3 Treatment of HES and CEL, NOS: reduced from 3 to 2 mcg/kg/week.120 A lower starting dose of 90 Corticosteroids, hydroxyurea, and interferon-alpha mcg/kg weekly (e.g., 1–1.5 mcg/kg weekly) is better tolerated based on the experience of PEG-IFN-a-2a in PV and ET.121,122 Side effects of For patients with strictly defined HES (e.g., exclusion of all other possi- short- and longer-acting formulations of IFN-a are usually dose- ble causes of hypereosinophilia), corticosteroids (e.g., prednisone 1 mg/ dependent and include can include fatigue and flu-like symptoms, kg) are the mainstay of therapy and are effective in producing rapid transaminitis, cytopenias, depression, hypothyroidism, and peripheral reductions in the eosinophil count. However, therapy can be compli- neuropathy. Unlike hydroxyurea which is a teratogen, interferon-alpha cated by side effects in those patients requiring long-term treatment to is considered safe for use in pregnancy. suppress eosinophilia and organ damage. In a retrospective analysis, Hematologic benefit has been observed with second- and third- 141/188 (75%) HES patients received corticosteroids as initial mono- line agents, including vincristine,123,124 cyclophosphamide,125 and eto- therapy with 85% of these individuals achieving a complete or partial poside.126,127 Responses to 2-chlorodeoxyadenosine alone128 or in response after one month of treatment.20 In this series, the median combination with cytarabine,129 and cyclosporin-A130,131 have also maximal dose was 40 mg (5 - 625 mg), the median maintenance dose been reported in HES, with a discontinuation rate of 82% with CSA in was 10 mg daily (range 1–40 mg daily) and the duration of therapy one series due to poor tolerance.20 ranged from 2 months to 20 years. In another retrospective series, the In selected cases, patients with CEL, NOS or HES may benefit median starting dose of prednisone was 30 mg daily (range 5–85 mg), from imatinib, usually administered at higher doses (> 400 mg daily).132 and the maintenance dose ranged from 5 mg twice weekly to 60 mg However, hematologic responses in this group are more often partial, daily. Twenty-one of 33 patients (64%) exhibited a complete resolution short-lived, and may reflect drug-related myelosuppression.9,10 Rare of eosinophilia, 5 patients (15%) achieved a 50% reduction, and 7 complete responses may represent diagnostically occult PDGFRA or patients (21%) were resistant or intolerant to corticosteroids.110 With PDGFRB mutations or other unknown pathogenetic targets.133 Clinical symptom control and reduction of the eosinophil count to below trials with novel agents should always be considered. 1500/mm3, corticosteroids can usually be tapered. Recrudescence of symptoms, signs of organ damage, and/or significant increase of the 4.3.1 | Summary eosinophil count with a prednisone dose > 10 mg daily is an indication Corticosteroids are potent anti-eosinophil agents with established effi- for addition of other agents. cacy in HES and should be considered first-line treatment. Similar to Hydroxyurea is an effective first-line agent for HES which may be other MPNs, hydroxyurea can serve as effective palliative chemother- used in conjunction with corticosteroids or in steroid nonrespond- apy to control leukocytosis and eosinophilia, but with no proven role in ers.19,21,111 A typical starting dose is 500 - 1000 mg daily. Hydroxyurea favorably altering the natural history of HES or CEL, NOS. Based on a was used in 64/188 patients (34%) in the retrospective study; among limited published literature, IFN-a has demonstrated hematologic 18 patients receiving hydroxuyrea as monotherapy, 13 patients (72%) responses and reversion of organ injury in patients with HES and CEL. GOTLIB ET AL. AJH | 1253

The logic of using IFN-a in CEL is partly extrapolated from its efficacy placebo every 4 weeks for 36 weeks. No adverse events were signifi- in other MPNs such as CML, as well as PV and ET, and evidence for cantly more frequent with mepolizumab compared to placebo. A signif- cytogenetic remitting activity. Although typically used as a second line- icantly higher proportion of mepolizumab-treated HES patients versus agent in HES steroid-failures, IFN-a could be used as initial therapy in placebo were able to achieve the primary efficacy endpoint of a daily patients with contra-indications or intolerance to steroid therapy. The prednisone dose of 10 mg daily for at least 8 consecutive weeks. In a optimal dose and duration of IFN-a therapy in HES is unknown and is long-term follow of 78 patients treated for a mean exposure of 251 tailored to individual response and tolerability. 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 4.4 | Treatment of lymphocyte-variant patients were prednisone-free without other HES medications for  12 139 hypereosinophilia consecutive weeks. Mepolizumab is not currently approved by the FDA for HES (approved only for severe eosinophilic asthma), but is cur- Patients with clonal population(s) of T-cells with an aberrant immuno- rently available on a compassionate use basis (clinicalTrials.gov Identi- phenotype and/or cytokine production should initially be treated with fier NCT00244686) for individuals with life-threatening HES who have corticosteroids. Patients who are refractory to therapy or exhibit failed prior therapies. a relapse may be considered for treatment with IFN- or steroid-sparing Reslizumab is a humanized anti-IL5 IgG4 mAb currently in clinical immunosuppressive agents. Among 16 lymphocyte-variant hypereosi- trials for pediatric subjects with eosinophilic esophagitis and for 1 nophilia patients with the aberrant CD3-CD4 immunophenotype, all patients with eosinophilic asthma, but has not yet been evaluated responded to corticosteroids, but 16 ultimately required steroid- extensively in HES.140 In a double-blind, placebo-controlled, random- 55 sparing agents. Hydroxyurea and imatinib are less likely to demon- ized trial, reslizumab significantly reduced intraepithelial esophageal strate efficacy in this lymphocyte-variant of hypereosinophilia com- eosinophil counts in children and adolescents with eosinophilic esopha- pared to myeloproliferative forms of the disease which can be very gitis, but symptom improvement was observed in both treatment responsive to these drugs as discussed above. Elevated serum IgE and groups.141 Benralizumab is an anti-IL5 receptor antibody that has been TARC levels were associated with responsiveness to steroids in the shown to reduce the annual asthma exacerbation rate in two phase III 20 lymphocyte-variant of hypereosinophilia. trials of patients with severe, uncontrolled eosinophilic asthma142,143 and is currently under evaluation for patients with HES (clinicaltrials. 4.4.1 | Summary gov identifier: NCT02130882). Corticosteroids are first-line therapy in patients with hypereosinophilia It is unknown whether mepolizumab or other anti-IL5 antibody in whom a clonal population of T-cells with an abnormal immunophe- approaches have a role in WHO-defined eosinophilic myeloid disor- notype are identified and other causes of an elevated eosinophil count ders. However, preclinical models suggest a pathobiologic rationale for are excluded. their use. Mice expressing FIP1L1-PDGFRA in their bone marrow cells only develop a general myeloproliferative disease.87 In contrast, 4.5 | Antibody approaches for HES expression of FIP1L1-PDGFRA together with overexpression of IL-5 4.5.1 | Mepolizumab mimics eosinophilic disease much better in mice with typical features of HES such as tissue infiltration of eosinophils.144 Anti-IL-5 antibody approaches have been studied in HES based on the cytokine’s role as a differentiation, activation, and survival factor for 4.5.2 | Alemtuzumab eosinophils. Mepolizumab is a fully humanized monoclonal IgG anti- Alemtuzumab is an anti-CD52 monoclonal antibody that has been eval- body that inhibits binding of IL-5 to the a chain of the IL-5 receptor uated in idiopathic HES based on expression of the CD52 antigen on 134 expressed on eosinophils. In HES patients, regression of constitu- eosinophils.145,146 Similar to mepolizumab, it has not been formally tional symptoms, eosinophilic dermatologic lesions, and improvements evaluated in myeloid-related eosinophilias. In patients with refractory FEV1 measurements in individuals with pulmonary disease have been HES, alemtuzumab administered intravenously at a dose of 5–30 mg 135–137 observed with anti-IL-5 antibody therapy. Among the few once to thrice weekly, elicited a complete hematologic remission (CHR) patients studied, responses have not been predicted by pretreatment in 10/12 subjects (83%), with 2 patients achieving a partial remis- serum IL-5 levels or presence of FIP1L1-PDGFRA. Rebound eosino- sion.147 Patients with CHR who received maintenance alemtuzumab philia, accompanied by increases in serum IL-5 levels, has been noted therapy exhibited significantly longer time to progression than patients in some cases, and tachyphylaxis has been observed with repeated who were only observed. Eleven patients relapsed (only one while on 137 doses without development of neutralizing antibodies. In the largest maintenance), and 6 were re-challenged with alemtuzumab. Five (83%) study of HES patients to date, the safety and steroid-sparing effects of achieved second CHR after a median of 3.5 weeks, for a median dura- mepolizumab was evaluated in a randomized, double-blind, placebo- tion of 123 weeks.148 controlled trial of 85 FIP1L1-PDGFRA-negative patients.138 Blood eosinophil levels were stabilized at <1000 cells/mm3 on 20–60 mg/ 4.5.3 | Summary day prednisone during a run-in period of up to 6 weeks. Patients were Use of anti-IL-5 and anti-CD52 antibody approaches in the treatment subsequently randomized to intravenous mepolizumab 750 mg or of HES remain investigational. Potential benefits include resolution of 1254 | AJH GOTLIB ET AL. eosinophilia and disease-related symptomology, and a steroid-sparing of myelofibrosis) may have a role in patients with eosinophilic disease. effect (mepolizumab). However, with discontinuation of therapy, bene- For example, rare patients with hypereosinophilia have been found to fits appear to be short-lived and the potential for rebound eosinophilia carry the JAK2 V617F activating mutation.50,170,171 More germane to exists. Maintenance therapy with these antibodies is generally required eosinophil biology is the finding that the JAK2 pathway mediates anti- to sustain responses. apoptosis signals in eosinophils in response to GM-CSF and IL-5,172,173 in addition to FIP1L1-PDGFRa.174 Inhibition of this signaling cascade 5 | TRANSPLANTATION may be a useful therapeutic approach across eosinophilic disorders regardless of their subtype. In addition, the finding that PDGF receptor Bone marrow/peripheral blood stem cell allogeneic transplantation has fusion oncogenes skew proliferation and differentiation toward the been attempted in patients with aggressive disease. Disease-free sur- eosinophil lineage in a process that requires NF-jB suggests the possi- vival ranging from 8 months to 5 years has been reported149–154 with bility for new treatments that target this pathway.175 one patient relapsing at 40 months.154 Allogeneic transplantation using nonmyeloablative conditioning regimens have been reported in three CONFLICT OF INTERESTS – patients, with remission duration of 3 12 months at the time of last Dr. Gotlib receives honoraria, serves on an advisory board, and 155,156 reported follow-up. In one patient who underwent an allogeneic receives funding from Incyte, Inc. for administration of clinical trials. stem cell transplantation from an HLA-matched sibling, the patient was disease free at 3 years, and there was no evidence of the FIP1L1- REFERENCES PDGFRA fusion which was present at diagnosis.157 Despite success in [1] Crane MM, Chang CM, Kobayashi MG, et al. Incidence of myelo- selected cases, the role of transplantation in HES is not well proliferative hypereosinophilic syndrome in the Unites States and established. an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol. 2010;126:179–181. 6 | SUPPORTIVE CARE AND SURGERY [2] Gotlib J, Cools J. Five years since the discovery of the FIPL1- PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. Leukemia. 2008;22:1999–2010. Leukapheresis can elicit transient reductions in high leukocyte and [3] Jovanovic JV, Score J, Waghorn K, et al. Low-dose imatinib mesylate 158–160 eosinophil counts, but is not an effective maintenance therapy. leads to rapid induction of major molecular responses and achieve- Splenectomy has been performed for hypersplenism-related abdominal ment of complete molecular remission in FIP1L1-PDGFRA-positive pain and splenic infarction, but is not considered standard treat- chronic eosinophilic leukemia. Blood. 2007;109:4635–4640. ment.22,161 Anticoagulants and anti-platelet agents have demonstrated [4] Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA variable success in preventing recurrent thromboembolism.22,162,163 fusion: prevalence and clinicopathologic correlates in 89 consecu- tive patients with moderate to severe eosinophilia. Blood. 2004; Advanced cardiac disease is less common today in patients with 104:3038–3045. eosinophilic disease. Cardiac surgery can extend the life of patients [5] Pardanani A, Ketterling RP, Li CY, et al. FIP1L1-PDGFRA in eosino- with late-stage heart disease manifested by endomyocardial fibrosis, philic disorders: prevalence in routine clinical practice, long-term mural thrombosis, and valvular insufficiency,19,21 Mitral and/or tricus- experience with imatinib therapy, and a critical review of the litera- pid valve repair or replacement164–168 and endomyocardectomy for ture. Leuk Res. 2006;30:965–970. late-stage fibrotic heart disease165,169 can improve cardiac function. [6] Wynn SR, Sachs MI, Keating MU, et al. Idiopathic hypereosino- philic syndrome in a 5 1= -month-old infant. J Pediatr. 1987;111: Bioprosthetic devices are generally preferred over their mechanical 2 94–97. counterparts because of the reduced frequency of valve thrombosis. [7] Bakhshi S, Hamre M, Mohamed AM, et al. t(5;9)(q11;q34): a novel familial translocation involving Abelson oncogene and association 7 | CONCLUDING REMARKS with hypereosinophilia. J Pediatr Hematol Oncol. 2003;25:82–84. [8] Rives S, Alcorta I, Toll T, et al. Idiopathic hypereosinophilic syn- A more sophisticated understanding of the cellular and molecular basis drome in children: report of a 7-year-old boy with FIP1L1- PDGFRA rearrangement. J Pediatr Hematol Oncol. 2005;27:663– of eosinophilic disorders has translated into more biologically-oriented 665. classification schemes which carry therapeutic implications. In this [9] Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by regard, imatinib for has dramatically reversed the poor-prognosis of fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of patients previously diagnosed as “HES” and who likely represented a imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. significant portion of older series of patients who exhibited a poor 2003;348:1201–1214. prognosis. Corticosteroids, interferon-alpha, hydroxyurea/other chem- [10] Baccarani M, Cilloni D, Rondoni M, et al. The efficacy of imatinib otherapy, and targeted antibodies can elicit clinical benefit in the pri- mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosi- nophilic syndrome. Results of a multicenter prospective study. mary eosinophilias, but response durability is variable, and treatment is Haematologica. 2007;92:1173–1179. often complicated by both short- and long-term side effects. Regarding [11] Brigden M, Graydon C. Eosinophilia detected by automated blood future directions, the recently approved JAK1/2 inhibitor ruxolitinib cell counting in ambulatory North American outpatients. Incidence (and other JAK inhibitors currently being evaluated in phase I-III trials and clinical significance. Arch Pathol Lab Med. 1997;121:963–967. GOTLIB ET AL. AJH | 1255

[12] Rothenberg ME. Eosinophilia. N Engl J Med . 1998;338:1592– [31] Mendez-Sanchez N, Chavez-Tapia NC, Vazquez-Elizondo G, et al. 1600. Eosinophilic gastroenteritis: a review. Dig Dis Sci. 2007;52:2904–2911. [13] Pardanani A, Patnaik MM, Tefferi A. Eosinophilia: secondary, clonal [32] Kawasaki A, Mizushima Y, Matsui S, et al. A case of T-cell lym- and idiopathic. Br J Haematol. 2006;133:468–492. phoma accompanying marked eosinophilia, chronic eosinophilic [14] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the pneumonia and eosinophilic pleural effusion. A case report. Tumori. – World Health Organization classification of myeloid neoplasms and 1991;77:527 530. acute leukemia. Blood. 2016;127:2391–2405. [33] Endo M, Usuki K, Kitazume K, et al. Hypereosinophilic syndrome ’ [15] Bain BJ, Gilliland DG, Horny H-P, et al. Myeloid and lymphoid in Hodgkin s disease with increased granulocyte-macrophage col- – neoplasms with eosinophilia and abnormalities of PDGFRA, ony-stimulating factor. Ann Hematol. 1995;71:313 314. PDGFRB, or FGFR1. In: Swerdlow S, Harris NL, Stein H, Jaffe ES, [34] Catovksy D, Bernasconi C, Verdonck PJ, et al. The association of Theile J, Vardiman JW, eds. World Health Organization Classification eosinophilia with lymphoblastic leukaemia or lymphoma: a study of of Tumours. Pathology and Genetics of Tumours of Haematopoietic seven patients. Br J Haematol. 1980;45:523–534. – and Lymphoid Tissues. Lyon, France: IARC Press: 2008:68 73. [35] Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a [16] Bain BJ, Gilliland DG, Horny H-P, et al. Chronic eosinophilic leu- surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocy- kaemia, not otherwise specified. In: Swerdlow S, Harris NL, Stein tosis associated with eosinophilia and predicts response to imatinib H, Jaffe ES, Theile J, Vardiman JW, eds. World Health Organization mesylate therapy. Blood. 2003;102:3093–3096. Classification of Tumours. Pathology and Genetics of Tumours of Hae- [36] Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels matopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008: identify a subset of patients with a myeloproliferative variant of 51–53. idiopathic hypereosinophilic syndrome associated with tissue fibro- [17] Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syn- sis, poor prognosis, and imatinib responsiveness. Blood. 2003;101: drome. Analysis of fourteen cases with review of the literature. 4660–4666. Medicine (Baltimore). 1975;54:1–27. [37] Schwaab J, Jawhar M, Naumann N, et al. Diagnostic challenges in [18] Valent P, Klion D, Horny HP, et al. Contemporary consensus proposal the work up of hypereosinophilia: pifalls in bone marrow core on criteria and classification of eosinophilic disorders and related syn- biopsy interpretation. Ann Hematol. 2016;95:557–562. dromes. J Allergy Clin Immunol. 2012;130(3):607–612.e9. [38] Metzgeroth G, Walz C, Score J, et al. Recurrent finding of the [19] Fauci AS, Harley JB, Roberts WC, et al. The idiopathic hypereosi- FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute mye- nophilic syndrome. Clinical, pathophysiologic, and therapeutic con- loid leukemia and lymphoblastic T-cell lymphoma. Leukemia. 2007; siderations. Ann Intern Med. 1982;97:78–92. 21:1183–1188. [20] Ogbogu PU, Bochner BS, Butterfield JH, et al. Hypereosinophilic [39] Elling C, Erben P, Walz C, et al. Novel imatinib-sensitive PDGFRA- syndromes: a multicenter, retrospective analysis of clinical charac- activating point mutations in hypereosinophilic syndrome induce teristics and response to therapy. J Allergy Clin Immunol. 2009;124: growth factor independence and leukemia-like disease. Blood. 1319–1325. 2011;117:2935–2943. [21] Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. [40] Greipp PT, Dewald GW, Tefferi A. Prevalence, breakpoint distribu- Blood. 1994;83:2759–2779. tion, and clinical correlates of t(5;12). Cancer Genet Cytogenet. [22] Spry CJ, Davies J, Tai PC, et al. Clinical features of fifteen patients 2004;153:170–172. with the hypereosinophilic syndrome. Q J Med. 1983;52:1–22. [41] Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood. [23] Lefebvre C, Bletry O, Degoulet P, et al. Prognostic factors of 2017;129:704–714. hypereosinophilic syndrome. Study of 40 cases. Ann Med Interne [42] Xiao S, Nalabolu SR, Aster JC, et al. FGFR1 is fused with a novel (Paris). 1989;140:253–257. zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syn- [24] Flaum MA, Schooley RT, Fauci AS, et al. A clinicopathologic corre- drome. Nat Genet. 1998;18:84–87. lation of the idiopathic hypereosinophilic syndrome. Blood. 1981; [43] Reiter A, Sohal J, Kulkarni S, et al. Consistent fusion of ZNF198 to 58:1012–1020. the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) [25] Gotlib J, Cools J, Malone JM, et al. The FIP1L1-PDGFRa fusion myeloproliferative syndrome. Blood. 1999;92:1735–1742. tyrosine kinase in hypereosinophilic syndrome and chronic eosino- [44] Popovici C, Adelaide J, Ollendorff V, et al. Fibroblast growth factor philic leukemia: implications for diagnosis, classification, and man- receptor 1 is fused to FIM in stem-cell myeloproliferative disorder agement. Blood. 2004;103:2879–2891. with t(8;13). Proc Natl Acad Sci USA. 1998;95:5712–5717. [26] Tanino M, Kitamura K, Ohta G, et al. Hypereosinophilic syndrome [45] Smedley D, Hamoudi R, Clark J, et al. The t(8;13)(p11;q11–12) with extensive myocardial involvement and mitral valve thrombus rearrangement associated with an atypical myeloproliferative disor- – instead of mural thrombi. Acta Pathol Jpn. 1983;33:1233 1242. der fuses the fibroblast growth factor receptor 1 gene to a novel [27] Radford DJ, Garlick RB, Pohlner PG. Multiple valvar replacement gene RAMP. Hum Mol Genet. 1998;7:637–642. – for hypereosinophilic syndrome. Cardiol Young. 2002;12:67 70. [46] Chung A, Hou Y, Ohgami R, et al. A novel TRIP11-FLT3 fusion in [28] Ommen SR, Seward JB, Tajik AJ. Clinical and echocardiographic a patients with a myeloid/lymphoid neoplasm with eosinophilia. features of hypereosinophilic syndromes. Am J Cardiol. 2000;86: Cancer Genet 2017;216–217:10–15. – 110 113. [47] Wang SA, Hasserjian RP, Tam W, et al. Bone marrow morphology [29] Ganeva M, Gancheva T, Lazarova R, et al. Carbamazepine-induced is a strong discriminator between chronic eosinophilic leukemia, drug reaction with eosinophilia and systemic symptoms (DRESS) not otherwise specified from reactive idiopathic hypereosinophilic syndrome: report of four cases and brief review. Int J Dermatol. syndrome. Haematologica. 2017;102:1352–1360. – 2008;47:853 860. [48] Simon HU, Plotz SG, Dummer R, et al. Abnormal clones of T cells [30] Campos LE, Pereira LF. Pulmonary eosinophilia. J Bras Pneumol. producing interleukin-5 in idiopathic hypereosinophilia. N Engl J 2009;35:561–573. Med. 1999;341:1112–1120. 1256 | AJH GOTLIB ET AL.

[49] Roufosse F, Cogan E, Goldman M. Recent advances in pathogene- [67] Kitano K, Ichikawa N, Shimodaira S, et al. Eosinophilia associated sis and management of hypereosinophilic syndromes. Allergy. with clonal T-cell proliferation. Leuk Lymphoma. 1997;27:335–342. – 2004;59:673 689. [68] Pardanani A, Lim KH, Lasho TL, et al. Prognostically relevant [50] Schwaab J, Umbach R, Metzgeroth G, et al. KIT D816V and JAK2 breakdown of 123 patients with systemic mastocytosis associated V617F mutations are seen recurrently in hypereosinophilia of with other myeloid malignancies. Blood. 2009;114:3769–3772. – unknown significance. Am J Hematol. 2015;90:774 777. [69] Wimazal F, Germing U, Kundi M, et al. Evaluation of the prognostic [51] Wang SA, Tam W, Tsai AG, et al. Targeted next-generation significance of eosinophilia and basophilia in a larger cohort of patients sequencing identifies a subset of idiopathic hypereosinophilic syn- with myelodysplastic syndromes. Cancer. 2010;116:2372–2381. drome with features similar to chronic eosinophilic leukemia, not [70] Matsushima T, Handa H, Yokohama A, et al. Prevalence and clini- – otherwise specified. Mod Pathol. 2016;29:854 864. cal characteristics of myelodysplastic syndrome with bone marrow [52] Cogan E, Schandene L, Crusiaux A, et al. Brief report: clonal prolif- eosinophilia or basophilia. Blood. 2003;101:3386–3390. eration of type 2 helper T cells in a man with the hypereosino- [71] Ackerman SJ, Butterfield JH. Eosinophilia, eosinophil-associated – philic syndrome. N Engl J Med. 1994;330:535 538. diseases, chronic eosinophilic leukemia, and the hypereosinophilic [53] Simon HU, Yousefi S, Dommann-Scherrer CC, et al. Expansion of syndromes. In: Hoffman R, Benz Jr., E, Shattil SJ, Furie B, Cohen cytokine-producing CD4-CD8- T cells associated with abnormal Fas HJ, Silberstein LE, McGlave P, eds. Hematology. 4th ed. Philadel- expression and hypereosinophilia. JExpMed.1996;183:1071–1082. phia: Churchill Livingstone; 2005. [54] Brugnoni D, Airo P, Rossi G, et al. CD41 T-cell population able to [72] Brito-Babapulle F. The eosinophilias, including the idiopathic secrete large amounts of interleukin-5. Blood. 1996;87:1416– hypereosinophilic syndrome. Br J Haematol. 2003;121:203–223. 1422. [73] Schaller JL, Burkland GA. Case report: rapid and complete control [55] Lefevre G, Copin MC, Staumont-Salle D, et al. The lymphoid vari- of idiopathic hypereosinophilia with imatinib mesylate. MedG- ant of hypereosinophilic syndrome: study of 21 patients with enMed. 2001;3:9. 1 CD3-CD4 aberrant T-cell phenotype. Medicine (Baltimore). 2014; [74] Gleich GJ, Leiferman KM, Pardanani A, et al. Treatment of hyper- – 93:255 266. eosinophilic syndrome with imatinib mesilate. Lancet. 2002;359: [56] Roufosse F, Schandene L, Sibille C, et al. T-cell receptor- 1577–1578. independent activation of clonal Th2 cells associated with chronic [75] Ault P, Cortes J, Koller C, et al. Response of idiopathic hypereosi- – hypereosinophilia. Blood. 1999;94:994 1002. nophilic syndrome to treatment with imatinib mesylate. Leuk Res. [57] Bank I, Amariglio N, Reshef A, et al. The hypereosinophilic syn- 2002;26:881–884. 1 drome associated with CD4 CD3- helper type 2 (Th2) lympho- [76] Griffin JH, Leung J, Bruner RJ, et al. Discovery of a fusion kinase – cytes. Leuk Lymphoma. 2001;42:123 133. in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc [58] Klion AD, Meija R, Cowen EW, et al. Chronic active Epstein-Barr Natl Acad Sci USA. 2003;100:7830–7835. virus infection: a novel cause of lymphocytic variant hypereosino- [77] Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal – philic syndrome. Blood. 2013;121:2364 2366. of myelofibrosis in response to imatinib mesylate treatment in [59] Roufosse F. Hypereosinophilic syndrome variants: diagnostic and patients with the myeloproliferative variant of hypereosinophilic therapeutic considerations. Haematologica. 2009;94:1188–1193. syndrome. Blood. 2004;103:473–478. [60] Helbig G, Wieczorkiewicz A, Dziaczkowska-Suszek J, et al. T-cell [78] Helbig G, Stella-Holowiecka B, Majewski M, et al. A single weekly abnormalities are present at high frequencies at high frequencies dose of imatinib is sufficient to induce and maintain remission of in patients with hypereosinophilic syndrome. Haematologica. 2009; chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing 94:1236–1241. patients. Br J Haematol. 2008;141:200–204. [61] DeLavareille A, Roufosse F, Schmid-Grendelmeier P, et al. High [79] Legrand F, Renneville A, Macintyre E, et al. The spectrum of FIP1L1- serum thymus and activation-regulated chemokine levels in the PDGFRA-associated chronic eosinophilic leukemia: new insights lymphocytic variant of the hypereosinophilic syndrome. J Allergy based on a survey of 44 cases. Medicine (Baltimore). 2013;92:e1–e9. – Clin Immunol. 2002;110:476 479. [80] Pardanani A, D’souza A, Knudson RA, et al. Long-term follow-up [62] Podjasek HC, Butterfield JH. Mortality in hypereosinophilic syn- of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival drome: 19 years of experience at Mayo Clinic with a review of the and clinical outcome. Leukemia. 2012;26:2439–2441. – literature. Leuk Res. 2013;37:392 395. [81] Klion AD, Robyn J, Maric I, et al. Relapse following discontinuation [63] Pardanani A, Lashi T, Wassie E, et al. Predictors of survival in of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic WHO-defined hypereosinophilic syndrome and idiopathic hypereo- eosinophilic leukemia: implications for optimal dosing. Blood. 2007; sinophilia and the role of next-generation sequencing. Leukemia. 110:3552–3556. – 2016;30:1924 1926. [82] Helbig G, Kyrcz-Krzemien S. Cessation of imatinib mesylate may [64] Helbig G, Soja A, Bartkowska-Chrobok A, et al. Chronic eosino- lead to sustained hematologic and molecular remission in FIP1L1- philic leukemia-not otherwise specified has a poor prognosis with PDGFRA-mutated hypereosinophilic syndrome. Am J Hematol. unresponsiveness to conventional treatment and high risk of acute 2014;89:115. – transformation. Am J Hematol. 2012;87:643 645. [83] Von Bubnoff N, Sandherr M, Schlimok G, et al. Myeloid blast crisis [65] Brugnoni D, Airo P, Tosoni C, et al. CD3-CD41 cells with a Th2- evolving during imatinib treatment of an FIP1L1-PDGFRalpha- like pattern of cytokine production in the peripheral blood of a positive chronic myeloproliferative disease with prominent eosino- patient with cutaneous T cell lymphoma. Leukemia. 1997;11:1983– philia. Leukemia. 2004;19:286–287. 1985. [84] Ohnishi H, Kandabashi K, Maeda Y, et al. Chronic eosinophilic leu- [66] Roufosse F, Schandene L, Sibille C, et al. Clonal Th2 lymphocytes kaemia with FIP1L1-PDGFRA fusion and T6741 mutation that in patients with the idiopathic hypereosinophilic syndrome. Br J evolved from Langerhans cell histiocytosis with eosinophilia after Haematol. 2000;109:540–548. chemotherapy. Br J Haematol. 2006;134:547–549. GOTLIB ET AL. AJH | 1257

[85] Lierman E, Michaux L, Beullens E, et al. FIP1L1-PDGFRalpha cytogenetic remission in t(8;9)(p22;p24)/PCM1-JAK2-positive D842V, a novel panresistant mutant, emerging after treatment of chronic eosinophilic leukemia. Blood. 2012;120:1529–1531. FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent [103] Rumi E, Milosevic JD, Casetti I, et al. Efficacy of ruxolitinib in – sorafenib. Leukemia. 2009;23:845 851. chronic eosinophilic leukemia associated with a PCM1-JAK2 [86] Bradeen HA, Eide CA, O’hare T, et al. Comparison of imatinib fusion gene. J Clin Oncol. 2013;31:e269–e271. mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an [104] Rumi E, Milosevic JD, Selleslag D, et al. Efficacy of ruxolitinib in N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high effi- myeloid neoplasms with PCM1-JAK2 fusion gene. Ann Hematol. – cacy of drug combinations. Blood. 2006;108:2332 2338. 2015;94:1927–1928. [87] Cools J, Stover EH, Boulton CL, et al. PKC412 overcomes resist- [105] Schwaab J, Knut M, Haferlach C, et al. Limited duration of complete ance to imatinib in a murine model of FIP1L1-PDGFRalpha- remission on ruxolitinib in myeloid neoplasms with PCM1-JAK2 and induced myeloproliferative disease. Cancer Cell. 2003;3:459–469. BCR-JAK2 fusion genes. Ann Hematol. 2015;94:233–238. [88] Lierman E, Folens C, Stover EH, et al. Sorafenib is a potent inhibi- [106] Walz C, Erben P, Ritter M, et al. Response of ETV6-FLT3-positive tor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1- myeloid/lymphoid neoplasm with eosinophilia to inhibitors of PDGFRalpha T674I mutant. Blood. 2006;108:1374–1376. FMS-like tyrosine kinase 3. Blood. 2011;118:2239–2242. [89] Stover EH, Chen J, Lee BH, et al. The small molecule tyrosine [107] Falchi L, Mehrotra M, Newberry KJ, et al. ETV6-FLT3 fusion gene- kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1- positive, eosinophilia-associated myeloproliferative neoplasm suc- PDGFRalpha in vitro and in vivo. Blood. 2005;106:3206–3213. cessfully treated with sorafenib and allogeneic stem cell transplant. [90] von Bubnoff N, Gorantla SP, Thone S, et al. The FIP1L1-PDGFRA Leukemia. 2014;28:2090–2092. T674I mutation can be inhibited by the tyrosine kinase inhibitor [108] Pardanani A, Reeder T, Porrata L, et al. Imatinib therapy for hyper- AMN107 (nilotinib). Blood. 2006;107:4970–4971. eosinophilic syndrome and other eosinophilic disorders. Blood. [91] Metzgeroth G, Erben P, Martin H, et al. Limited clinical activity of 2003;101:3391–3397. nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosino- [109] Pitini V, Arrigo C, Azzarello D, et al. Serum concentration of car- philic leukemia with imatinib-resistant T674I mutation. Leukemia. diac troponin T in patients with hypereosinophilic syndrome 2012;26:162–164. treated with imatinib is predictive of adverse outcomes. Blood. [92] Simon D, Salemi S, Yousefi S, et al. Primary resistance to imatinib 2003;102:3456–3457. in Fip1-like 1-platelet-derived growth factor receptor alpha- [110] Helbig G, Wisnieswka-Piaty K, Francuz T, et al. Diversity of clinical positive eosinophilic leukemia. J Allergy Clin Immunol. 2008;121: manifestations and response to corticosteroids for idiopathic 1054–1056. hypereosinophilic syndrome: retrospective study in 33 patients. [93] Gorantla SP, Zirlik K, Reiter A, et al. F604S exchange in FIP1L1-PDGFRA Leuk Lymphoma. 2013;54:807–811. enhances FIP1L1-PDGFRA stability via SHP-2 and SRC: a novel mode of [111] Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic kinase inhibitor resistance. Leukemia. 2015;29:1763–1770. syndrome. Ann Intern Med. 1978;89:167–172. [94] Cross DM, Cross NC, Burgstaller S, et al. Durable responses to [112] Quiquandon I, Claisse JF, Capiod JC, et al. Alpha-interferon and imatinib in patients with PDGFRB fusion gene-positive and BCR- hypereosinophilic syndrome with trisomy 8: karyotypic remission. ABL-negative chronic myeloproliferative disorders. Blood. 2007; Blood. 1995;85:2284–2285. 109:61–64. [113] Luciano L, Catalano L, Sarrantonio C, et al. aIFN–induced hemato- [95] Cheah CY, Burbury K, Apperley JF, et al. Patients with myeloid logic and cytogenetic remission in chronic eosinophilic leukemia malignancies bearing PDGFRB fusion genes achieve durable long- with t(1;5). Haematologica. 1999;84:651–653. term remissions with imatinib. Blood. 2014;123:3574–3577. [114] Yamada O, Kitahara K, Imamura K, et al. Clinical and cytogenetic [96] Metzgeroth G, Schwaab J, Gosenca D, et al. Long-term follow-up remission induced by interferon-a in a patient with chronic eosin- of treatment with imatinib in eosinophilia-associated myeloid/ ophilic leukemia associated with a unique t(3;9;5) translocation. lymphoid neoplasms with PDGFR rearrangements in blast phase. Am J Hematol. 1998;58:137–141. Leukemia. 2013;27:2254–2256. [115] Malbrain ML, Van den Bergh H, Zachee P. Further evidence for [97] Chen J, DeAngelo DJ, Kutok JL, et al. PKC412 inhibits the zinc fin- the clonal nature of the idiopathic hypereosinophilic syndrome: ger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase complete haematological and cytogenetic remission induced by and is active in treatment of stem cell myeloproliferative disorder. interferon-alpha in a case with a unique chromosomal abnormality. Proc Natl Acad Sci U S A. 2004;101:14479–14484. Br J Haematol. 1996;92:176–183. [98] Chase A, Bryant C, Score J, Cross NC. Ponatinib as targeted ther- [116] Butterfield JH, Gleich GJ. Response of six patients with idiopathic apy for FGFR1 fusions associated with the 8p11 myeloprolifera- hypereosinophilic syndrome to interferon alpha. J Allergy Clin tive syndrome. Haematologica. 2013;98:103–106. Immunol. 1994;94:1318–1326. [99] Ren M, Qin H, Ren R, Cowell JK. Ponatinib suppresses the devel- [117] Ceretelli S, Capochiani E, Petrini M. Interferon-alpha in the idio- opment of myeloid and lymphoid malignancies associated with pathic hypereosinophilic syndrome: consideration of five cases. FGFR1 abnormalities. Leukemia. 2013;27:32–40. Ann Hematol. 1998;77:161–164. [100] Khodadoust MS, Luo B, Medeiros BC, et al. Clinical activity of [118] Yoon TY, Ahn GB, Chang SH. Complete remission of hypereosino- ponatinib in a patient with FGFR1-rearranged mixed phenotype philic syndrome after interferon-alpha therapy: report of a case acute leukemia. Leukemia. 2016;30:947–950. and literature review. J Dermatol. 2000;27:110–115. [101] Kreil S, Ades L, Bommer M, et al. Limited efficacy of ponatinib in [119] Butterfield JH. Interferon treatment for hypereosinophilic syndromes myeloproliferative neoplasms associated with FGFR1 fusion genes. and systemic mastocytosis. Acta Haematol. 2005;114:26–40. Blood. 2015;126. [Abstract 2812]. [120] Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-a-2b therapy in [102] Lierman E, Selleslag D, Smits S, et al. Ruxolitinib inhibits trans- BCR-ABL-negative myeloproliferative disorders. Final result of a forming JAK2 fusion proteins in vitro and induces complete phase 2 study. Cancer. 2007;110:2012–2018. 1258 | AJH GOTLIB ET AL.

[121] Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alpha- [140] Walsh GM. Reslizumab, a humanized anti-IL-5 mAb for the treat- 2a induces complete hematologic and molecular responses with low ment of eosinophil-mediated inflammatory conditions. Curr Opin toxicity in polycythemia vera. Blood. 2008;112:3065–3072. Mol Ther. 2009;11:329–336. [122] Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated [141] Reslizumab in children and adolescents with eosinophilic esophagi- interferon-alpha-2a yields high rates of hematologic and molecular tis: results of a double-blind, randomized, placebo-controlled trial. response in patients with advanced essential thrombocythemia J Allergy Clin Immunol. 2012;129:456–463. 463.e1–3. – and polycythemia vera. J Clin Oncol. 2009;27:5418 5424. [142] Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of [123] Cofrancesco E, Cortellaro M, Pogliani E, et al. Response to vincris- benralizumab for patients with severe asthma uncontrolled with tine treatment in a case of idiopathic hypereosinophilic syndrome high-dosage corticosteroids and long-acting b2-agonists with multiple clinical manifestations. Acta Haematol. 1984;72:21– (SIROCCO): a randomised, multicenter, placebo-controlled phase 3 25. trial. Lancet. 2016;388:2115–2127. [124] Sakamoto K, Erdreich-Epstein A, deClerck Y, et al. Prolonged clini- [143] FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti- cal response to vincristine treatment in two patients with hyper- interleukin-5 receptor a monoclonal antibody, as add-on treatment eosinophilic syndrome. Am J Pediatr Hematol Oncol. 1992;14:348– for patients with severe, uncontrolled, eosinophilic asthma (CAL- 351. IMA): a randomised, double-blind, placebo-controlled phase 3 trial. [125] Lee JH, Lee JW, Jang CS, et al. Successful cyclophosphamide ther- Lancet. 2016;388:2128–2141. apy in recurrent eosinophilic colitis associated with hypereosino- [144] Yamada Y, Rothenberg ME, Lee AW, et al. The FIP1L1-PDGFRA philic syndrome. Yonsei Med J. 2002;43:267–270. fusion gene cooperates with IL-5 to induce murine hypereosino- [126] Smit AJ, van Essen LH, de Vries EG. Successful long-term control philic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like dis- of idiopathic hypereosinophilic syndrome with etoposide. Cancer. ease. Blood. 2006;107:4071–4079. 1991;67:2826–2827. [145] Pitini V, Teti D, Arrigo C, Righi M, et al. Alemtuzumab therapy for [127] Bourrat E, Lebbe C, Calvo F. Etoposide for treating the hypereosi- refractory idiopathic hypereosinophilic syndrome with abnormal T- nophilic syndrome. Ann Intern Med. 1994;121:899–900. cells: a case report. Br J Haematol. 2004;127:477. [128] Ueno NT, Zhao S, Robertson LE, et al. 2-chlorodeoxyadenosine [146] Sefcick A, Sowter D, DasGupta E, et al. Alemtuzumab therapy for therapy for idiopathic hypereosinophilic syndrome. Leukemia. refractory idiopathic hypereosinophilic syndrome. Br J Haematol. 1997;11:1386–1390. 2004;124:558–559. [129] Jabbour E, Verstovsek S, Giles F, et al. 2-chlorodeoxyadenosine [147] Verstovsek S, Tefferi A, Kantarjian H, et al. Alemtuzumab therapy and cytarabine combination therapy for idiopathic hypereosino- for hypereosinophilic syndrome and chronic eosinophilic leukemia. philic syndrome. Cancer. 2005;104:541–546. Clin Cancer Res. 2009;15:368–373. [130] Zabel P, Schlaak M. Cyclosporin for hypereosinophilic syndrome. [148] Strati P, Cortes J, Faderl S, et al. Long-term follow-up of patients with Ann Hematol. 1991;62:230–231. hypereosinophilic syndrome treated with Alemtuzumab, an anti- CD52 antibody. Clin Lymphoma Myeloma Leuk. 2013;13:287–291. [131] Nadarajah S, Krafchik B, Roifman C, et al. Treatment of hypereosi- nophilic syndrome in a child using cyclosporine: implication for a [149] Vazquez L, Caballero D, Canizo CD, et al. Allogeneic peripheral primary T-cell abnormality. Pediatrics. 1997;99:630–633. blood cell transplantation for hypereosinophilic syndrome with myelofibrosis. Bone Marrow Transplant. 2000;25:217–218. [132] Butterfield JH. Success of short-term, higher-dose imatinib mesy- late to induce clinical response in FIP1L1-PDGFRalpha-negative [150] Chockalingam A, Jalil A, Shadduck RK, et al. Allogeneic peripheral hypereosinophilic syndrome. Leuk Res. 2009;33:1127–1129. blood stem cell transplantation for hypereosinophilic syndrome with severe cardiac dysfunction. Bone Marrow Transplant. 1999;23: [133] Helbig G, Hus M, Halasz, et al. Imatinib mesylate may induce long- 1093–1094. term clinical response in FIP1L1-PDGFRa-negative hypereosino- philic syndrome. Med Oncol. 2011;29:1073–1076. [151] Basara N, Markova J, Schmetzer B, et al. Chronic eosinophilic leu- kemia: successful treatment with an unrelated bone marrow trans- [134] Hart TK, Cook RM, Zia-Amirhosseini P, et al. Preclinical efficacy plantation. Leuk Lymphoma. 1998;32:189–193. and safety of mepolizumab (SB—240563), a humanized monoclo- nal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immu- [152] Sigmund DA, Flessa HC. Hypereosinophilic syndrome: successful nol. 2001;108:250–257. allogeneic bone marrow transplantation. Bone Marrow Transplant. – [135] Plotz SG, Simon HU, Darsow U, et al. Use of an anti-interleukin-5 1995;15:647 648. antibody in the hypereosinophilic syndrome with eosinophilic der- [153] Esteva-Lorenzo FJ, Meehan KR, Spitzer TR, et al. Allogeneic bone matitis. N Engl J Med. 2003;349:2334–2339. marrow transplantation in a patient with hypereosinophilic syn- – [136] Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5 drome. Am J Hematol. 1996;51:164 165. (mepolizumab) therapy for hypereosinophilic syndrome. J Allergy [154] Sadoun A, Lacotte L, Delwail V, et al. Allogeneic bone marrow Clin Immunol. 2004;113:115–119. transplantation for hypereosinophilic syndrome with advanced – [137] Klion AD, Law MA, Noel P, et al. Safety and efficacy of the mono- myelofibrosis. Bone Marrow Transplant. 1997;19:741 743. clonal anti-interleukin-5 antibody SCH55700 in the treatment of [155] Juvonen E, Volin L, Kopenen A, et al. Allogeneic blood stem cell patients with hypereosinophilic syndrome. Blood. 2004;103:2939– transplantation following non-myeloablative conditioning for 2941. hypereosinophilic syndrome. Bone Marrow Transplant. 2002;29: – [138] Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of 457 458. patients with the hypereosinophilic syndrome with mepolizumab. [156] Ueno NT, Anagnostopoulos A, Rondon G, et al. Successful non- N Engl J Med. 2008;358:1215–1228. myeloablative allogeneic transplantation for treatment of idiopathic – [139] Roufosse FE, Kahn JE, Gleich GJ, et al. Long-term safety of mepo- hypereosinophilic syndrome. Br J Haematol. 2002;119:131 134. lizumab for the treatment of hypereosinophilic syndromes. [157] Halaburda K, Preizner W, Szatkowski D, et al. Allogeneic bone J Allergy Clin Immunol. 2013;131:461–467. marrow transplantation for hypereosinophilic syndrome: long-term GOTLIB ET AL. AJH | 1259

follow-up with eradication of FIP1L1-PDGFRA fusion transcript. [169] Chandra M, Pettigrew RI, Eley JW, et al. Cine-MRI-aided endo- Bone Marrow Transplant. 2006;38:319–320. myocardectomy in idiopathic hypereosinophilic syndrome. Ann – [158] Blacklock HA, Cleland JF, Tan P, et al. The hypereosinophilic syn- Thorac Surg. 1996;62:1856 1858. drome and leukapheresis. Ann Intern Med. 1979;91:650–651. [170] Jones AV, Kreil S, Zoi K. Widespread occurrence of the JAK2 [159] Davies J, Spry C. Plasma exchange or leukapheresis in the hyper- V617F mutation in chronic myeloproliferative disorders. Blood. – eosinophilic syndrome. Ann Intern Med. 1982;96:791. 2005;106:2162 2168. [160] Chambers LA, Leonard SS, Whatmough AE, et al. Management of [171] Helbig G, Stella-Holowiecka B, Mjewski M, et al. Interferon alpha hypereosinophilic syndrome with chronic plasma- and leukaphere- induces a good molecular response in a patient with chronic eosin- sis. Prog Clin Biol Res. 1990;337:83–85. ophilic leukemia (CEL) carrying the JAK2V617F point mutation. Haematologica. 2007;92:e118–e119. [161] Narayan S, Ezughah F, Standen GR, et al. Idiopathic hypereosino- philic syndrome associated with cutaneous infarction and deep [172] Simon HU, Yousefi S, Dibbert B, et al. Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced venous thrombosis. Br J Dermatol. 1993;148:817–820. via Jak2 tyrosine kinase in eosinophils. Eur J Immunol. 1997;27: [162] Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idi- 3536–3539. opathic hypereosinophilic syndrome. Ann Intern Med. 1985;102: [173] Miike S, Nakao A, Hiraguri M, et al. Involvement of JAK2, but not PI 109–114. 3-kinase/AKT and MAP kinase pathways, in anti-apoptotic signals [163] Johnston AM, Woodcock BE. Acute aortic thrombosis despite of GM-CSF of human eosinophils. J Leukoc Biol. 1999;65:700–706. anticoagulant therapy in idiopathic hypereosinophilic syndrome. [174] Li B, Zhang G, Li C, et al. Identification of JAK2 as a mediator of J R Soc Med. 1998;91:492–493. FIP1L1-PDGFRA-induced eosinophil growth and function in CEL. [164] Radford DJ, Garlick RB, Pohlner PG. Multiple valvar replacement PLoS One. 2012;7:e34912. for hypereosinophilic syndrome. Cardiol Young. 2002;12:67–70. [175] Montano-Almendras CP, Essaghir A, Schoemans H, et al. ETV6- [165] Harley JB, McIntosh XL, Kirklin JJ, et al. Atrioventricular valve PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic replacement in the idiopathic hypereosinophilic syndrome. Am J progenitor proliferation and differentiation into eosinophils: role of – Med. 1982;73:77 81. NF-jB. Haematologica. 2012;97:1064–1072. [166] Hendren WG, Jones EL, Smith MD. Aortic and mitral valve replacement in idiopathic hypereosinophilic syndrome. Ann Thorac Surg. 1988;46:570–571. How to cite this article: Gotlib J. World Health Organization- [167] Cameron J, Radford DJ, Howell J, et al. Hypereosinophilic heart defined eosinophilic disorders: 2017 update on diagnosis, risk disease. Med J Aust. 1985;143:408–410. stratification, and management. Am J Hematol. 2017;92:1243– [168] Kiris I, Okutan H, Peker T, et al. Mitral valve replacement in a 1259. https://doi.org/10.1002/ajh.24880 patient with idiopathic hypereosinophilic syndrome and pulmonary artery hypertension. J Card Surg. 2009;24:80–82.