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CME Information: World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management Author: Jason Gotlib, M.D., M.S. CME Editor: Ayalew Tefferi, M.D.
If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com
䊏 Accreditation and Designation Statement: Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. Understand the 2008 World Health Organization semi-molecular classification of eosinophilic disorders 2. Understand the algorithm for the diagnosis of eosinophilic conditions and treatment options based on disease subtype.
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Author: Jason Gotlib, M.D., M.S. discloses honoraria for advisory board services and funding for clinical trials from Incyte, Inc. CME Editor: Ayalew Tefferi, M.D. has no conflicts of interest to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
䊏 Instructions on Receiving Credit This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test. Follow these steps to earn credit:
Log on to www.wileyhealthlearning.com Read the target audience, educational objectives, and activity disclosures. Read the activity contents in print or online format. Reflect on the activity contents. Access the CME Exam, and choose the best answer to each question. Complete the required evaluation component of the activity. Claim your Certificate.
This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months. C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.00032
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World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management Jason Gotlib* Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Diagnosis: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1’, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. Risk-adapted therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., 5,000/mm3) [11–13]. The classification of eosinophilic diseases was revised in the 2008 World Health Organization scheme of myeloid neoplasms (Table I). In recognition of the growing list of recurrent, molecularly defined primary eosinophilias, a new major category was created, “Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA), plateletderived growth factor receptor beta (PDGFRB), or fibroblast growth factor receptor 1 (FGFR1)” (Table I) [14]. Within the major WHO category of myeloproliferative neoplasms (MPNs), “chronic eosinophilic leukemia-not otherwise specified” (CEL-NOS) is one of eight disease entities within this group (Table I) [15]. CEL-NOS is operationally defined by absence of the Philadelphia chromosome or a rearrangement involving PDGFRA/B and FGFR1, and the exclusion of other acute or chronic primary marrow neoplasms associated with eosinophilia such as acute myeloid leukemia (AML), myelodysplastic TABLE I. 2008 World Health Organization (WHO) Classification of Myeloid Malignancies
1. Acute myeloid leukemia and related disorders 2. Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia, not otherwise specified Mastocytosis Myeloproliferative neoplasms, unclassifiable 3. Myelodysplastic syndromes (MDS) Refractory cytopenia with uni-lineage dysplasia 䊏 Refractory anemia 䊏 Refractory neutropenia 䊏 Refractory thrombocytopenia Refractory anemia with ring sideroblasts Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts (RAEB) 䊏 RAEB-1 䊏 RAEB-2 Myelodysplastic syndrome with isolated del(5q) Myelodysplastic syndrome, unclassifiable 4. MDS/MPN Chronic myelomonocytic leukemia 䊏 CMML-1 䊏 CMML-2 Atypical chronic myeloid leukemia, BCR-ABL1 negative Juvenile myelomonocytic leukemia MDS/MPN, unclassifiable 䊏 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) 5. Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement Myeloid neoplasms associated with PDGFRB rearrangement Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities.
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syndrome (MDS), systemic mastocytosis (SM), classic MPNs (chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), and MDS/MPN overlap disorders (e.g., chronic myelomonocytic leukemia, CMML; Table II). CEL-NOS is histologically characterized by an increase in blasts in the bone marrow or blood (but fewer than 20% to exclude acute leukemia as a diagnosis), and/or there is an evidence for clonality in the eosinophil lineage [15]. A diagnosis of idiopathic HES requires exclusion of all primary and secondary causes of hypereosinophilia as well as lymphocyte-variant HE (Table II). The modern definition of HES remains a vestige of the historical criteria outlined by Chusid et al. in 1975: the AEC is >1,500/mm3 for more than 6 months, and tissue damage is present [16]. The requirement that eosinophilia persist for more than 6 months is less consistently embraced today because of the availability of more sophisticated tools to rapidly evaluate eosinophilia and the need for some patients to receive expedited treatment to minimize organ damage. In contrast to “HES,” “idiopathic HE” is the preferred term when end-organ damage is absent [15]. The pool of classically defined idiopathic HES patients has diminished due to an increasing proportion of cases which have been reassigned as clonal marrow disorders. HES may therefore be considered a provisional diagnosis until a primary or secondary cause of eosinophilia is recognized. In 2011, the Working Conference on Eosinophil Disorders and Syndromes proposed a new terminology for eosinophilic syndromes [17]. The panel recommended the higher level term “HE” for persistent and marked eosinophilia (AEC > 1,500/mm3). In turn, HE subtypes were divided into a hereditary (familial) variant (HEFA), HE of undetermined significance (HEUS), primary (clonal/neoplastic) HE produced by clonal/neoplastic eosinophils (HEN), and secondary (reactive) HE (HER). HEUS was introduced as a novel term in lieu of “idiopathic HE.” Any HE (not just idiopathic) associated with organ damage is referred to as “HES” with specific variants designated by subscripts (e.g., HESUS, HESN, and HESR). Additional recommendations advanced by the consensus panel are summarized in their report.
Clinical presentation and diagnosis The varied clinical presentations of primary eosinophilias/HES reflect their heterogeneous pathophysiology. In two retrospective series published in 1982 and 2009, eosinophilia was an incidental finding in 12 and 6% of patients, respectively [18,19]. The most common presenting signs and symptoms were weakness and fatigue (26%), cough (24%), dyspnea (16%), myalgias or angioedema (14%), rash or fever (12%), and rhinitis (10%) [17]. In HES, leukocytosis (e.g., 20,000–30,000/mm3 or higher) with peripheral eosinophilia in the range of 30–70% is a common finding [16,18–20]; the aforementioned retrospective analysis of 188 patients from 2009 observed a mean peak eosinophil count of 6,600/mm3 with a range of 1,500– 400,000/mm3 [18]. Other hematologic findings include peripheral blood or bone marrow neutrophilia, basophilia, myeloid immaturity, and both mature and immature eosinophils with varying degrees of dysplasia [20–22]. In one series, anemia was present in 53% of patients, thrombocytopenia was more common than thrombocytosis (31% vs. 16%), and bone marrow eosinophilia ranged from 7 to 57% (mean 33%) [22]. Marrow findings of Charcot–Leyden crystals, and sometimes increased blasts and marrow fibrosis, are also observed [22]. Essentially all organ systems may be susceptible to the effects of sustained eosinophilia [reviewed in 23]. During follow-up of patients with HE, dermatologic involvement was also the most common clinical manifestation reported in 69% of patients, followed by pulmonary (44%) and gastrointestinal (38%) manifestations. Cardiac disease
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TABLE II. 2008 World Health Organization Classification of Eosinophilic Disorders Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 Diagnostic criteria of an MPNa with eosinophilia associated with FIP1L1-PDGFRA A myeloproliferative neoplasm with prominent eosinophilia AND Presence of a FIP1L1-PDGFRA fusion geneb Diagnostic criteria of MPN associated with ETV6-PDGFRB fusion gene or other rearrangement of PDGFRB A myeloproliferative neoplasm, often with prominent eosinophilia and sometimes with neutrophilia or monocytosis AND Presence of t(5;12)(q31q33;p12) or a variant translocationc or, demonstration of an ETV6-PDGFRB fusion gene or rearrangement of PDGFRB Diagnostic criteria of MPN or acute leukemia associated with FGFR1 rearrangement A myeloproliferative neoplasm with prominent eosinophilia and sometimes with neutrophilia or monocytosis OR Acute myeloid leukemia or precursor T-cell or precursor B-cell lymphoblastic leukemia/lymphoma (usually associated with peripheral blood or bone marrow eosinophilia) AND Presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts, or both Chronic Eosinophilic Leukemia, Not Otherwise Specified (NOS) 1. There is eosinophilia (eosinophil count >1.5 3 109/L) 2. There is no Ph chromosome or BCR-ABL fusion gene or other myeloproliferative neoplasms (PV, ET, PMF, systemic mastocytosis) or MDS/MPN (CMML or atypical CML) 3. There is no t(5;12)(q31q35;p13) or other rearrangement of PDGFRB 4. There is no FIP1L1-PDGFRA fusion gene or other rearrangement of PDGFRA 5. There is no rearrangement of FGFR1 6. The blast cell count in the peripheral blood and bone marrow is less than 20% and there is no inv(16)(p13q22) or t(16;16)(p13;q22) or other feature diagnostic of AML 7. There is a clonal cytogenetic or molecular genetic abnormality, or blast cells are more than 2% in the peripheral blood or more than 5% in the bone marrow. Idiopathic Hypereosinophilic Syndrome (HES) Exclusion of the following: 1. Reactive eosinophilia 2. Lymphocyte-variant hypereosinophilia (cytokine-producing, immunophenotypically aberrant T-cell population) 3. Chronic eosinophilic leukemia, NOS 4. WHO-defined myeloid malignancies associated eosinophilia (e.g., MDS, MPNs, MDS/MPNs, or AML) 5. Eosinophilia-associated MPNs or AML/ALL with rearrangements of PDGFRA, PDGFRB, or FGR1. 6. The absolute eosinophil count of >1,500/mm3 must persist for at least 6 months and tissue damage must be present. If there is no tissue damage, idiopathic hypereosinophilia is the preferred diagnosis. a
Patients presenting with acute myeloid leukemia or lymphoblastic leukemia/lymphoma with eosinophilia and a FIP1L1-PDGFRA fusion gene are also assigned to this category b If appropriate molecular analysis is not available, this diagnosis should be suspected if there is a Ph-negative MPN with the hematological features of chronic eosinophilic leukemia associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase and increased bone marrow mast cells. c Because t(5;12)(q31q33;p12) does not always lead to an ETV6-PDGFRB fusion gene, molecular confirmation is highly desirable. If molecular analysis is not available, this diagnosis should be suspected if there is a Ph-negative MPN associated with eosinophilia and with a translocation with a 5q31–33 breakpoint.
unrelated to hypertension, atherosclerosis, or rheumatic disease was eventually identified in 20% of patients (only 6% at the time of initial presentation) [19]. Progressive heart failure is a proto-typical example of eosinophil-mediated organ injury. It involves a multistep pathophysiological process involving eosinophil infiltration of cardiac tissue and release of toxic mediators from eosinophils [reviewed in 18,24]. Endocardial damage with resulting platelet thrombus can lead to mural thrombi and increased embolic risk. In the later fibrotic stage, fibrous thickening of the endocardial lining can evolve to a restrictive cardiomyopathy [18,24]. Valvular insufficiency results from mural endocardial thrombosis and fibrosis involving leaflets of the mitral or tricuspid valves [25–27].
䊏 Diagnosis Step 1: Exclude secondary (reactive) causes of eosinophilia Secondary eosinophilia has numerous causes which may require diagnostic evaluation by a cadre of different subspecialty consultants. In developing countries, eosinophilia most commonly derives from infections, particularly tissue-invasive parasites [13]. Allergy/atopy and hypersensitivity conditions, drug reaction, collagen-vascular disease
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[e.g., Churg–Strauss Syndrome, granulomatosis with polyangiitis (Wegener’s), systemic lupus erythematosus], pulmonary eosinophilic diseases (e.g., idiopathic acute or chronic eosinophilia pneumonia, tropical pulmonary eosinophilia, allergic bronchopulmonary aspergillosis, etc.), allergic gastroenteritis (with associated peripheral eosinophilia), and metabolic conditions such as adrenal insufficiency are diagnostic considerations in the appropriate clinical context [28–30]. Nonmyeloid malignancies may be associated with secondary eosinophilia which results from the production of cytokines such as IL-3, IL-5, and GMCSF which promote eosinophil differentiation and survival. For example, these cytokines may be elaborated from malignant cells in T-cell lymphomas [31], Hodgkin’s disease [32], and acute lymphoblastic leukemias [33]. Rare conditions associated with eosinophilia include familial eosinophilia whose genetic basis remains unknown, hyper IgE Syndrome, Omenn Syndrome, episodic angioedema and eosinophilia (Gleich’s syndrome), and eosinophilia-myalgia syndrome (e.g., possibly related to tryptophan ingestion, or of historical interest, the epidemic of toxic-oil syndrome) [17]. Repeated ova and parasite testing, stool culture, and antibody testing for specific parasites (e.g., Strongyloides) is paramount for identifying infectious etiologies in the appropriate clinical context. Additional laboratory and imaging tests (e.g., chest-x-ray, electrocardiogram and echocardiography, CT scan of the chest, abdomen/pelvis) are guided by the patient’s travel history, presenting
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Figure 1. Diagnostic and treatment algorithm based on 2008 WHO classification of eosinophilic disorders.
symptoms, and findings on physical examination. For eosinophilic lung diseases, pulmonary function testing, bronchoscopy, serologic tests [e.g., aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis (ABPA)] may be obtained to further characterize lung involvement.
Step 2: Evaluate for primary (clonal) eosinophilia If secondary causes of eosinophilia are excluded, the work-up should proceed to the evaluation of a primary bone marrow disorder. Examination of the blood smear and blood tests (e.g., circulating blasts, dysplastic cells, monocytosis, elevated serum B12, or tryptase level) in conjunction with bone marrow morphologic, cytogenetic, and immunophenoytpic analysis will help ascertain whether the differential diagnosis of eosinophilia includes a well-defined WHO mye-
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loid neoplasm such as SM, chronic myelogenous leukemia, acute myelogenous leukemia (especially the historically defined M2 and M4 Eo French-American-British subtypes), MDS, or MDS/MPN overlap disorder (e.g., CMML). Although not formally included in the WHO monograph, the term “myeloproliferative variant of HE” has been used to refer to some of these marrow-derived eosinophilic myeloid malignancies because of clinicopathologic similarity to CML and the BCR-ABL-negative MPNs [9,23]. Laboratory evaluation of primary eosinophilia should begin with screening of the peripheral blood for the FIP1L1-PDGFRA gene fusion (by RT-PCR or interphase/metaphase FISH; Fig. 1). FISH probes that hybridize to the region between the FIP1L1 and PDGFRA genes are used to detect the presence of the cytogenetically occult 800-kb deletion on 4q12 that results in FIP1L1-PDGFRA [9,34]. As
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the CHIC2 gene is located in this deleted genetic segment, this widely available clinical test is referred to as “FISH for the CHIC2 deletion” [34]. In instances where FIP1L1-PDGFRA screening is not available, evaluation of the serum tryptase can be a useful surrogate marker for FIP1L1-PDGFRA-positive disease as increased levels segregate with this molecular abnormality and myeloproliferative variants of HE [35]. FIP1L1-PDGFRA has also been identified histopathologically defined cases of SM with associated eosinophilia [4]. The bone marrows of such patients typically exhibit less dense clusters of mast cells by tryptase immunostaining are observed in SM with the highly prevalent KIT D816V mutation [4]. The FIP1L1-PDGFRA fusion has also been found in cases of AML and T-cell lymphoblastic lymphoma associated with eosinophilia [36]. In addition to dysregulation of PDGFRA by fusion to FIP1L1 or other partner genes, activating point mutations have been identified in PDGFRA in patients with HE [37]. Although there was variability in their transforming ability, injection of cells harboring these mutants into mice induced a leukemia-like disease. Imatinib treatment significantly decreased leukemic growth and prolonged survival [37]. Absence of the FIP1L1-PDGFRA fusion should prompt evaluation for other primary eosinophilias associated with recurrent molecular abnormalities. Molecular evidence for a PDGFRA, PDGFRB, or FGFR1 fusion gene is often accompanied by its abnormal karyotype equivalent: rearrangement of 4q12 (PDGFRA fusion partners besides FIP1L1), 5q31-33 (PDGFRB), or 8p11-13 (FGFR1) [14]. Despite the rare frequency (2% in the peripheral blood or >5% in the bone marrow, but 10 mg daily is an indication for addition of other agents. Hydroxyurea is an effective first-line agent for HES which may be used in conjunction with corticosteroids or in steroid nonresponders [18,24,93]. A typical starting dose is 500–1,000 mg daily. Hydroxyurea was used in 64/188 patients (34%) in the retrospective study; among 18 patients receiving hydroxuyrea as monotherapy, 13 patients (72%) achieved a complete or partial response [18]. When hydroxyurea was combined with corticosteroids, the overall response rate was 69%. Interferon-a (IFN-a) can produce hematologic and cytogenetic remissions in HES and CEL patients refractory to other therapies including prednisone and/or hydroxyurea [94–100], or can be used in conjunction with corticosteroids as a steroid-sparing agent for individuals requiring higher doses of prednisone. Some have advocated its use as initial therapy for these disorders [99]. In the retrospective study, 46/188 patients were treated with IFN-a (mostly in combination with glucocorticoids) with response rates of 50 and 75% as monotherapy or combination therapy, respectively [19]. The optimal starting or maintenance dose of IFN-a has not been well defined, but the initial dose required to control eosinophil counts often exceeds the doses needed to maintain a remission [101]. Initiation of therapy at one million units by subcutaneous injection thrice weekly (tiw) and gradual escalation of the dose to 3–4 million units tiw or higher may be required to control HE in some patients. Remissions have been associated with improvement in clinical symptoms and organ disease, including hepatosplenomegaly [95,99], cardiac and thromboembolic complications [94,96], mucosal ulcers [97], and skin involvement [100]. Treatment of four HES patients with PEG-IFN-a2b among a larger cohort of BCR-ABL-negative MPN cohort resulted in one complete and one partial response, but side effects required that the initial study dose be reduced from 3 to 2 mcg/kg/week [102]. A lower starting dose of 90 mcg/kg weekly (e.g., 1–1.5 mcg/kg weekly) is better tolerated based on the experience of PEG-IFN-a-2a in PV and ET [103,104]. Side effects of short- and longer-acting formulations of IFN-a are usually dose dependent and include fatigue
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and flu-like symptoms, transaminitis, cytopenias, depression, hypothyroidism, and peripheral neuropathy. Unlike hydroxyurea which is a teratogen, interferon-alpha is considered safe for use in pregnancy. Hematologic benefit has been observed with second- and third-line agents, including vincristine [105–107], cyclophosphamide [108], and etoposide [109,110]. Responses to 2-chlorodeoxyadenosine alone [111] or in combination with cytarabine [112], and cyclosporin-A [113,114] have also been reported in HES, with a discontinuation rate of 82% with CSA in one series due to poor tolerance [19]. In selected cases, patients with CEL, NOS, or HES may benefit from imatinib, usually administered at higher doses (>400 mg daily) [115]. However, hematologic responses in this group are more often partial, short lived, and may reflect drug-related myelosuppression [9,10]. Rare complete responses may represent diagnostically occult PDGFRA or PDGFRB mutations or other unknown pathogenetic targets [116]. Clinical trials with novel agents should always be considered. Summary. Corticosteroids are potent antieosinophil agents with established efficacy in HES and should be considered first-line treatment. Similar to its use in other MPNs, hydroxyurea can serve as effective palliative chemotherapy to control leukocytosis and eosinophilia, but with no proven role in favorably altering the natural history of HES or CEL, NOS. Based on a limited published literature, IFN-a has demonstrated hematologic responses and reversion of organ injury in patients with HES and CEL. The logic of using IFN-a in CEL is partly extrapolated from its efficacy in other MPNs such as CML, as well as PV and ET, and evidence for cytogenetic remitting activity. Although typically used as a second-line agent in HES steroid failures, IFN-a could be used as initial therapy in patients with contra-indications or intolerance to steroid therapy. The optimal dose and duration of IFN-a therapy in HES is unknown and is tailored to individual response and tolerability.
Treatment of lymphocyte-variant HE Patients with clonal population(s) of T-cells with an aberrant immunophenotype and/or cytokine production should initially be treated with corticosteroids. Patients who are refractory to therapy or exhibit relapse may be considered for treatment with IFN-a or steroid-sparing immunosuppressive agents. Hydroxyurea and imatinib are less likely to demonstrate efficacy in this lymphocyte-variant of HE compared to myeloproliferative forms of the disease which can be very responsive to these drugs as discussed above. Elevated serum IgE and TARC levels were associated with responsiveness to steroids in the lymphocyte-variant of HE [19]. Summary. Corticosteroids are first-line therapy in patients with HE in whom a clonal population of T-cells with an abnormal immunophenotype are identified and other causes of an elevated eosinophil count are excluded.
Antibody approaches for HES Mepolizumab. Anti-IL-5 antibody approaches have been studied in HES based on the cytokine’s role as a differentiation, activation, and survival factor for eosinophils. Mepolizumab is a fully humanized monoclonal IgG antibody that inhibits binding of IL-5 to the a chain of the IL-5 receptor expressed on eosinophils [117]. In HES patients, regression of constitutional symptoms, eosinophilic dermatologic lesions, and improvements FEV1 measurements in individuals with pulmonary disease have been observed with anti-IL-5 antibody therapy [118–120]. Among the few patients studied, response has not been predicted by pretreatment serum IL-5 levels or presence of FIP1L1-PDGFRA. Rebound eosinophilia, accompanied by increases in serum IL-5 levels, has been noted in some cases, and tachyphylaxis has been observed with repeated doses without development of neutralizing antibodies [116]. In the largest study of HES patients to
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date, the safety and steroid-sparing effects of mepolizumab was evaluated in a randomized, double-blind, placebo-controlled trial of 85 FIP1L1-PDGFRA-negative patients [121]. Blood eosinophil levels were stabilized at
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CME Information: World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management Author: Jason Gotlib, M.D., M.S. CME Editor: Ayalew Tefferi, M.D.
If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com
䊏 Accreditation and Designation Statement: Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. Understand the 2008 World Health Organization semi-molecular classification of eosinophilic disorders 2. Understand the algorithm for the diagnosis of eosinophilic conditions and treatment options based on disease subtype.
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Author: Jason Gotlib, M.D., M.S. discloses honoraria for advisory board services and funding for clinical trials from Incyte, Inc. CME Editor: Ayalew Tefferi, M.D. has no conflicts of interest to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
䊏 Instructions on Receiving Credit This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test. Follow these steps to earn credit:
Log on to www.wileyhealthlearning.com Read the target audience, educational objectives, and activity disclosures. Read the activity contents in print or online format. Reflect on the activity contents. Access the CME Exam, and choose the best answer to each question. Complete the required evaluation component of the activity. Claim your Certificate.
This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months. C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.00032
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World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management Jason Gotlib* Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Diagnosis: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1’, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. Risk-adapted therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., 5,000/mm3) [11–13]. The classification of eosinophilic diseases was revised in the 2008 World Health Organization scheme of myeloid neoplasms (Table I). In recognition of the growing list of recurrent, molecularly defined primary eosinophilias, a new major category was created, “Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA), plateletderived growth factor receptor beta (PDGFRB), or fibroblast growth factor receptor 1 (FGFR1)” (Table I) [14]. Within the major WHO category of myeloproliferative neoplasms (MPNs), “chronic eosinophilic leukemia-not otherwise specified” (CEL-NOS) is one of eight disease entities within this group (Table I) [15]. CEL-NOS is operationally defined by absence of the Philadelphia chromosome or a rearrangement involving PDGFRA/B and FGFR1, and the exclusion of other acute or chronic primary marrow neoplasms associated with eosinophilia such as acute myeloid leukemia (AML), myelodysplastic TABLE I. 2008 World Health Organization (WHO) Classification of Myeloid Malignancies
1. Acute myeloid leukemia and related disorders 2. Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia, not otherwise specified Mastocytosis Myeloproliferative neoplasms, unclassifiable 3. Myelodysplastic syndromes (MDS) Refractory cytopenia with uni-lineage dysplasia 䊏 Refractory anemia 䊏 Refractory neutropenia 䊏 Refractory thrombocytopenia Refractory anemia with ring sideroblasts Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts (RAEB) 䊏 RAEB-1 䊏 RAEB-2 Myelodysplastic syndrome with isolated del(5q) Myelodysplastic syndrome, unclassifiable 4. MDS/MPN Chronic myelomonocytic leukemia 䊏 CMML-1 䊏 CMML-2 Atypical chronic myeloid leukemia, BCR-ABL1 negative Juvenile myelomonocytic leukemia MDS/MPN, unclassifiable 䊏 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) 5. Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement Myeloid neoplasms associated with PDGFRB rearrangement Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities.
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syndrome (MDS), systemic mastocytosis (SM), classic MPNs (chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), and MDS/MPN overlap disorders (e.g., chronic myelomonocytic leukemia, CMML; Table II). CEL-NOS is histologically characterized by an increase in blasts in the bone marrow or blood (but fewer than 20% to exclude acute leukemia as a diagnosis), and/or there is an evidence for clonality in the eosinophil lineage [15]. A diagnosis of idiopathic HES requires exclusion of all primary and secondary causes of hypereosinophilia as well as lymphocyte-variant HE (Table II). The modern definition of HES remains a vestige of the historical criteria outlined by Chusid et al. in 1975: the AEC is >1,500/mm3 for more than 6 months, and tissue damage is present [16]. The requirement that eosinophilia persist for more than 6 months is less consistently embraced today because of the availability of more sophisticated tools to rapidly evaluate eosinophilia and the need for some patients to receive expedited treatment to minimize organ damage. In contrast to “HES,” “idiopathic HE” is the preferred term when end-organ damage is absent [15]. The pool of classically defined idiopathic HES patients has diminished due to an increasing proportion of cases which have been reassigned as clonal marrow disorders. HES may therefore be considered a provisional diagnosis until a primary or secondary cause of eosinophilia is recognized. In 2011, the Working Conference on Eosinophil Disorders and Syndromes proposed a new terminology for eosinophilic syndromes [17]. The panel recommended the higher level term “HE” for persistent and marked eosinophilia (AEC > 1,500/mm3). In turn, HE subtypes were divided into a hereditary (familial) variant (HEFA), HE of undetermined significance (HEUS), primary (clonal/neoplastic) HE produced by clonal/neoplastic eosinophils (HEN), and secondary (reactive) HE (HER). HEUS was introduced as a novel term in lieu of “idiopathic HE.” Any HE (not just idiopathic) associated with organ damage is referred to as “HES” with specific variants designated by subscripts (e.g., HESUS, HESN, and HESR). Additional recommendations advanced by the consensus panel are summarized in their report.
Clinical presentation and diagnosis The varied clinical presentations of primary eosinophilias/HES reflect their heterogeneous pathophysiology. In two retrospective series published in 1982 and 2009, eosinophilia was an incidental finding in 12 and 6% of patients, respectively [18,19]. The most common presenting signs and symptoms were weakness and fatigue (26%), cough (24%), dyspnea (16%), myalgias or angioedema (14%), rash or fever (12%), and rhinitis (10%) [17]. In HES, leukocytosis (e.g., 20,000–30,000/mm3 or higher) with peripheral eosinophilia in the range of 30–70% is a common finding [16,18–20]; the aforementioned retrospective analysis of 188 patients from 2009 observed a mean peak eosinophil count of 6,600/mm3 with a range of 1,500– 400,000/mm3 [18]. Other hematologic findings include peripheral blood or bone marrow neutrophilia, basophilia, myeloid immaturity, and both mature and immature eosinophils with varying degrees of dysplasia [20–22]. In one series, anemia was present in 53% of patients, thrombocytopenia was more common than thrombocytosis (31% vs. 16%), and bone marrow eosinophilia ranged from 7 to 57% (mean 33%) [22]. Marrow findings of Charcot–Leyden crystals, and sometimes increased blasts and marrow fibrosis, are also observed [22]. Essentially all organ systems may be susceptible to the effects of sustained eosinophilia [reviewed in 23]. During follow-up of patients with HE, dermatologic involvement was also the most common clinical manifestation reported in 69% of patients, followed by pulmonary (44%) and gastrointestinal (38%) manifestations. Cardiac disease
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TABLE II. 2008 World Health Organization Classification of Eosinophilic Disorders Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 Diagnostic criteria of an MPNa with eosinophilia associated with FIP1L1-PDGFRA A myeloproliferative neoplasm with prominent eosinophilia AND Presence of a FIP1L1-PDGFRA fusion geneb Diagnostic criteria of MPN associated with ETV6-PDGFRB fusion gene or other rearrangement of PDGFRB A myeloproliferative neoplasm, often with prominent eosinophilia and sometimes with neutrophilia or monocytosis AND Presence of t(5;12)(q31q33;p12) or a variant translocationc or, demonstration of an ETV6-PDGFRB fusion gene or rearrangement of PDGFRB Diagnostic criteria of MPN or acute leukemia associated with FGFR1 rearrangement A myeloproliferative neoplasm with prominent eosinophilia and sometimes with neutrophilia or monocytosis OR Acute myeloid leukemia or precursor T-cell or precursor B-cell lymphoblastic leukemia/lymphoma (usually associated with peripheral blood or bone marrow eosinophilia) AND Presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement demonstrated in myeloid cells, lymphoblasts, or both Chronic Eosinophilic Leukemia, Not Otherwise Specified (NOS) 1. There is eosinophilia (eosinophil count >1.5 3 109/L) 2. There is no Ph chromosome or BCR-ABL fusion gene or other myeloproliferative neoplasms (PV, ET, PMF, systemic mastocytosis) or MDS/MPN (CMML or atypical CML) 3. There is no t(5;12)(q31q35;p13) or other rearrangement of PDGFRB 4. There is no FIP1L1-PDGFRA fusion gene or other rearrangement of PDGFRA 5. There is no rearrangement of FGFR1 6. The blast cell count in the peripheral blood and bone marrow is less than 20% and there is no inv(16)(p13q22) or t(16;16)(p13;q22) or other feature diagnostic of AML 7. There is a clonal cytogenetic or molecular genetic abnormality, or blast cells are more than 2% in the peripheral blood or more than 5% in the bone marrow. Idiopathic Hypereosinophilic Syndrome (HES) Exclusion of the following: 1. Reactive eosinophilia 2. Lymphocyte-variant hypereosinophilia (cytokine-producing, immunophenotypically aberrant T-cell population) 3. Chronic eosinophilic leukemia, NOS 4. WHO-defined myeloid malignancies associated eosinophilia (e.g., MDS, MPNs, MDS/MPNs, or AML) 5. Eosinophilia-associated MPNs or AML/ALL with rearrangements of PDGFRA, PDGFRB, or FGR1. 6. The absolute eosinophil count of >1,500/mm3 must persist for at least 6 months and tissue damage must be present. If there is no tissue damage, idiopathic hypereosinophilia is the preferred diagnosis. a
Patients presenting with acute myeloid leukemia or lymphoblastic leukemia/lymphoma with eosinophilia and a FIP1L1-PDGFRA fusion gene are also assigned to this category b If appropriate molecular analysis is not available, this diagnosis should be suspected if there is a Ph-negative MPN with the hematological features of chronic eosinophilic leukemia associated with splenomegaly, a marked elevation of serum vitamin B12, elevation of serum tryptase and increased bone marrow mast cells. c Because t(5;12)(q31q33;p12) does not always lead to an ETV6-PDGFRB fusion gene, molecular confirmation is highly desirable. If molecular analysis is not available, this diagnosis should be suspected if there is a Ph-negative MPN associated with eosinophilia and with a translocation with a 5q31–33 breakpoint.
unrelated to hypertension, atherosclerosis, or rheumatic disease was eventually identified in 20% of patients (only 6% at the time of initial presentation) [19]. Progressive heart failure is a proto-typical example of eosinophil-mediated organ injury. It involves a multistep pathophysiological process involving eosinophil infiltration of cardiac tissue and release of toxic mediators from eosinophils [reviewed in 18,24]. Endocardial damage with resulting platelet thrombus can lead to mural thrombi and increased embolic risk. In the later fibrotic stage, fibrous thickening of the endocardial lining can evolve to a restrictive cardiomyopathy [18,24]. Valvular insufficiency results from mural endocardial thrombosis and fibrosis involving leaflets of the mitral or tricuspid valves [25–27].
䊏 Diagnosis Step 1: Exclude secondary (reactive) causes of eosinophilia Secondary eosinophilia has numerous causes which may require diagnostic evaluation by a cadre of different subspecialty consultants. In developing countries, eosinophilia most commonly derives from infections, particularly tissue-invasive parasites [13]. Allergy/atopy and hypersensitivity conditions, drug reaction, collagen-vascular disease
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[e.g., Churg–Strauss Syndrome, granulomatosis with polyangiitis (Wegener’s), systemic lupus erythematosus], pulmonary eosinophilic diseases (e.g., idiopathic acute or chronic eosinophilia pneumonia, tropical pulmonary eosinophilia, allergic bronchopulmonary aspergillosis, etc.), allergic gastroenteritis (with associated peripheral eosinophilia), and metabolic conditions such as adrenal insufficiency are diagnostic considerations in the appropriate clinical context [28–30]. Nonmyeloid malignancies may be associated with secondary eosinophilia which results from the production of cytokines such as IL-3, IL-5, and GMCSF which promote eosinophil differentiation and survival. For example, these cytokines may be elaborated from malignant cells in T-cell lymphomas [31], Hodgkin’s disease [32], and acute lymphoblastic leukemias [33]. Rare conditions associated with eosinophilia include familial eosinophilia whose genetic basis remains unknown, hyper IgE Syndrome, Omenn Syndrome, episodic angioedema and eosinophilia (Gleich’s syndrome), and eosinophilia-myalgia syndrome (e.g., possibly related to tryptophan ingestion, or of historical interest, the epidemic of toxic-oil syndrome) [17]. Repeated ova and parasite testing, stool culture, and antibody testing for specific parasites (e.g., Strongyloides) is paramount for identifying infectious etiologies in the appropriate clinical context. Additional laboratory and imaging tests (e.g., chest-x-ray, electrocardiogram and echocardiography, CT scan of the chest, abdomen/pelvis) are guided by the patient’s travel history, presenting
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Figure 1. Diagnostic and treatment algorithm based on 2008 WHO classification of eosinophilic disorders.
symptoms, and findings on physical examination. For eosinophilic lung diseases, pulmonary function testing, bronchoscopy, serologic tests [e.g., aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis (ABPA)] may be obtained to further characterize lung involvement.
Step 2: Evaluate for primary (clonal) eosinophilia If secondary causes of eosinophilia are excluded, the work-up should proceed to the evaluation of a primary bone marrow disorder. Examination of the blood smear and blood tests (e.g., circulating blasts, dysplastic cells, monocytosis, elevated serum B12, or tryptase level) in conjunction with bone marrow morphologic, cytogenetic, and immunophenoytpic analysis will help ascertain whether the differential diagnosis of eosinophilia includes a well-defined WHO mye-
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loid neoplasm such as SM, chronic myelogenous leukemia, acute myelogenous leukemia (especially the historically defined M2 and M4 Eo French-American-British subtypes), MDS, or MDS/MPN overlap disorder (e.g., CMML). Although not formally included in the WHO monograph, the term “myeloproliferative variant of HE” has been used to refer to some of these marrow-derived eosinophilic myeloid malignancies because of clinicopathologic similarity to CML and the BCR-ABL-negative MPNs [9,23]. Laboratory evaluation of primary eosinophilia should begin with screening of the peripheral blood for the FIP1L1-PDGFRA gene fusion (by RT-PCR or interphase/metaphase FISH; Fig. 1). FISH probes that hybridize to the region between the FIP1L1 and PDGFRA genes are used to detect the presence of the cytogenetically occult 800-kb deletion on 4q12 that results in FIP1L1-PDGFRA [9,34]. As
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the CHIC2 gene is located in this deleted genetic segment, this widely available clinical test is referred to as “FISH for the CHIC2 deletion” [34]. In instances where FIP1L1-PDGFRA screening is not available, evaluation of the serum tryptase can be a useful surrogate marker for FIP1L1-PDGFRA-positive disease as increased levels segregate with this molecular abnormality and myeloproliferative variants of HE [35]. FIP1L1-PDGFRA has also been identified histopathologically defined cases of SM with associated eosinophilia [4]. The bone marrows of such patients typically exhibit less dense clusters of mast cells by tryptase immunostaining are observed in SM with the highly prevalent KIT D816V mutation [4]. The FIP1L1-PDGFRA fusion has also been found in cases of AML and T-cell lymphoblastic lymphoma associated with eosinophilia [36]. In addition to dysregulation of PDGFRA by fusion to FIP1L1 or other partner genes, activating point mutations have been identified in PDGFRA in patients with HE [37]. Although there was variability in their transforming ability, injection of cells harboring these mutants into mice induced a leukemia-like disease. Imatinib treatment significantly decreased leukemic growth and prolonged survival [37]. Absence of the FIP1L1-PDGFRA fusion should prompt evaluation for other primary eosinophilias associated with recurrent molecular abnormalities. Molecular evidence for a PDGFRA, PDGFRB, or FGFR1 fusion gene is often accompanied by its abnormal karyotype equivalent: rearrangement of 4q12 (PDGFRA fusion partners besides FIP1L1), 5q31-33 (PDGFRB), or 8p11-13 (FGFR1) [14]. Despite the rare frequency (2% in the peripheral blood or >5% in the bone marrow, but 10 mg daily is an indication for addition of other agents. Hydroxyurea is an effective first-line agent for HES which may be used in conjunction with corticosteroids or in steroid nonresponders [18,24,93]. A typical starting dose is 500–1,000 mg daily. Hydroxyurea was used in 64/188 patients (34%) in the retrospective study; among 18 patients receiving hydroxuyrea as monotherapy, 13 patients (72%) achieved a complete or partial response [18]. When hydroxyurea was combined with corticosteroids, the overall response rate was 69%. Interferon-a (IFN-a) can produce hematologic and cytogenetic remissions in HES and CEL patients refractory to other therapies including prednisone and/or hydroxyurea [94–100], or can be used in conjunction with corticosteroids as a steroid-sparing agent for individuals requiring higher doses of prednisone. Some have advocated its use as initial therapy for these disorders [99]. In the retrospective study, 46/188 patients were treated with IFN-a (mostly in combination with glucocorticoids) with response rates of 50 and 75% as monotherapy or combination therapy, respectively [19]. The optimal starting or maintenance dose of IFN-a has not been well defined, but the initial dose required to control eosinophil counts often exceeds the doses needed to maintain a remission [101]. Initiation of therapy at one million units by subcutaneous injection thrice weekly (tiw) and gradual escalation of the dose to 3–4 million units tiw or higher may be required to control HE in some patients. Remissions have been associated with improvement in clinical symptoms and organ disease, including hepatosplenomegaly [95,99], cardiac and thromboembolic complications [94,96], mucosal ulcers [97], and skin involvement [100]. Treatment of four HES patients with PEG-IFN-a2b among a larger cohort of BCR-ABL-negative MPN cohort resulted in one complete and one partial response, but side effects required that the initial study dose be reduced from 3 to 2 mcg/kg/week [102]. A lower starting dose of 90 mcg/kg weekly (e.g., 1–1.5 mcg/kg weekly) is better tolerated based on the experience of PEG-IFN-a-2a in PV and ET [103,104]. Side effects of short- and longer-acting formulations of IFN-a are usually dose dependent and include fatigue
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and flu-like symptoms, transaminitis, cytopenias, depression, hypothyroidism, and peripheral neuropathy. Unlike hydroxyurea which is a teratogen, interferon-alpha is considered safe for use in pregnancy. Hematologic benefit has been observed with second- and third-line agents, including vincristine [105–107], cyclophosphamide [108], and etoposide [109,110]. Responses to 2-chlorodeoxyadenosine alone [111] or in combination with cytarabine [112], and cyclosporin-A [113,114] have also been reported in HES, with a discontinuation rate of 82% with CSA in one series due to poor tolerance [19]. In selected cases, patients with CEL, NOS, or HES may benefit from imatinib, usually administered at higher doses (>400 mg daily) [115]. However, hematologic responses in this group are more often partial, short lived, and may reflect drug-related myelosuppression [9,10]. Rare complete responses may represent diagnostically occult PDGFRA or PDGFRB mutations or other unknown pathogenetic targets [116]. Clinical trials with novel agents should always be considered. Summary. Corticosteroids are potent antieosinophil agents with established efficacy in HES and should be considered first-line treatment. Similar to its use in other MPNs, hydroxyurea can serve as effective palliative chemotherapy to control leukocytosis and eosinophilia, but with no proven role in favorably altering the natural history of HES or CEL, NOS. Based on a limited published literature, IFN-a has demonstrated hematologic responses and reversion of organ injury in patients with HES and CEL. The logic of using IFN-a in CEL is partly extrapolated from its efficacy in other MPNs such as CML, as well as PV and ET, and evidence for cytogenetic remitting activity. Although typically used as a second-line agent in HES steroid failures, IFN-a could be used as initial therapy in patients with contra-indications or intolerance to steroid therapy. The optimal dose and duration of IFN-a therapy in HES is unknown and is tailored to individual response and tolerability.
Treatment of lymphocyte-variant HE Patients with clonal population(s) of T-cells with an aberrant immunophenotype and/or cytokine production should initially be treated with corticosteroids. Patients who are refractory to therapy or exhibit relapse may be considered for treatment with IFN-a or steroid-sparing immunosuppressive agents. Hydroxyurea and imatinib are less likely to demonstrate efficacy in this lymphocyte-variant of HE compared to myeloproliferative forms of the disease which can be very responsive to these drugs as discussed above. Elevated serum IgE and TARC levels were associated with responsiveness to steroids in the lymphocyte-variant of HE [19]. Summary. Corticosteroids are first-line therapy in patients with HE in whom a clonal population of T-cells with an abnormal immunophenotype are identified and other causes of an elevated eosinophil count are excluded.
Antibody approaches for HES Mepolizumab. Anti-IL-5 antibody approaches have been studied in HES based on the cytokine’s role as a differentiation, activation, and survival factor for eosinophils. Mepolizumab is a fully humanized monoclonal IgG antibody that inhibits binding of IL-5 to the a chain of the IL-5 receptor expressed on eosinophils [117]. In HES patients, regression of constitutional symptoms, eosinophilic dermatologic lesions, and improvements FEV1 measurements in individuals with pulmonary disease have been observed with anti-IL-5 antibody therapy [118–120]. Among the few patients studied, response has not been predicted by pretreatment serum IL-5 levels or presence of FIP1L1-PDGFRA. Rebound eosinophilia, accompanied by increases in serum IL-5 levels, has been noted in some cases, and tachyphylaxis has been observed with repeated doses without development of neutralizing antibodies [116]. In the largest study of HES patients to
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date, the safety and steroid-sparing effects of mepolizumab was evaluated in a randomized, double-blind, placebo-controlled trial of 85 FIP1L1-PDGFRA-negative patients [121]. Blood eosinophil levels were stabilized at
