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