Elsevier

Blood Reviews

Volume 23, Issue 4, July 2009, Pages 157-165
Blood Reviews

REVIEW
Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders

https://doi.org/10.1016/j.blre.2009.01.001Get rights and content

Abstract

Eosinophilia is a recurrent feature and diagnostic clue in several hematologic malignancies. In stem cell- and myelopoietic neoplasms, eosinophils are derived from the malignant clone, whereas in lymphoid neoplasms and reactive states, eosinophilia is usually triggered by eosinopoietic cytokines. Myeloid neoplasms typically presenting with eosinophilia include chronic myeloid leukemia, chronic eosinophilic leukemia (CEL), other myeloproliferative neoplasms, some acute leukemias, advanced mast cell disorders, and rare forms of myelodysplastic syndromes. Diagnostic evaluations in unexplained eosinophilia have to take these diagnoses into account. In such patients, a thorough hematologic work-up including bone marrow histology and immunohistochemistry, cytogenetics, molecular markers, and a complete staging of potentially affected organ systems has to be initiated. Endomyocardial fibrosis, the most dangerous cardiovascular complication of the hypereosinophilic state, is frequently detected in PDGFR-mutated neoplasms, specifically in FIP1L1/PDGFRA+ CEL, but is usually not seen in other myeloid neoplasms or reactive eosinophilia, even if eosinophilia is recorded for many years. Treatment of hypereosinophilic patients depends on the variant of disease, presence of end organ damage, molecular targets, and the overall situation in each case. In a group of patients, oncogenic tyrosine kinases (TK) such as FIP1L1/PDGFRA, can be employed as therapeutic targets by using imatinib or other TK-blocking agents.

Section snippets

Biology of eosinophils and reactive eosinophilia

Eosinophils are myelopoietic effector cells that produce and store a number of biologically active molecules, including eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil neurotoxin, lipid mediators (prostaglandins, leukotriens, and thromboxan A2), and cytokines such as tumor necrosis factor (TNF) alpha.[1], [2], [3] Once activated, eosinophils release their mediators and cytokines, thereby influencing homeostasis and tissue integrity.3 In case of massive and permanent

Diagnostic algorithm and initial investigations

Several different pathologic conditions may lead to an increased production and/or accumulation of reactive/non-neoplastic eosinophils. In most instances, an underlying cause is known or is revealed after initial investigations. Such investigations include a detailed case history, thorough physical examination, X-ray of chest (and lung function test if necessary), electrocardiogram and echocardiogram, ultrasound of abdomen, a complete blood count with microscopic differential count, and a

The hypereosinophilic syndrome (HES)

Major diagnostic criteria for the so called hypereosinophilic syndrome are (i) a permanent eosinophil count of >1500/μL (for at least 6 months) and (ii) the typical end organ damage.[29], [30], [31], [32], [33], [34] In addition, unrelated disorders and transient eosinophilia have to be excluded. Patients with HES may suffer from multiorgan involvement or from isolated end organ damage. In many cases, lung- or endomyocardial fibrosis is seen. In other patients, thrombosis, neurologic symptoms,

Diagnostic approach in patients with suspected hematologic neoplasm

In patients in whom eosinophilia is unlikely to be reactive and/or is accompanied by other blood count abnormalities or by typical end organ damage (HES), specific blood tests are performed, and the bone marrow is examined. Fig. 2 provides a diagnostic algorithm for these patients. Most molecular studies can be performed using peripheral blood and thus yield rapid diagnostic results.[25], [34], [35] Depending on clinical and blood findings, initial tests include markers indicative of (a) a stem

Chronic eosinophilic leukemia (CEL)

Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm defined by the following criteria: persistent eosinophilia (>1500/μL for at least 6 months) and molecular or/and cytogenetic evidence of monoclonal eosinophils, and/or presence of blast cells in the peripheral blood (>2%) or bone marrow (5–19%), and exclusion of all other hematologic and non-hematologic causes of eosinophilia, with recognition of the principle possibility of coexistence of two separate disorders (e.g.

Myeloproliferative and stem cell neoplasms, myelodysplastic syndromes (MDS), and overlap syndromes

Eosinophilia is typically found in various myeloproliferative neoplasms (MPN). In Philadelphia chromosome positive (Ph+) CML, eosinophilia and basophilia are almost always present at diagnosis, and often also when the disease progresses. In patients with typical JAK2 V617F+ MPN, eosinophilia is less frequently detected, but may also occur.25 However, in distinct variants of (atypical) MPN, namely those that develop on the basis of (in association with) an oncogenic form of PDGFRA, PDGFRB, or

Mast cell disorders – systemic mastocytosis (SM) and mast cell leukemia

Although indolent and aggressive variants of SM may be accompanied by eosinophilia (SM-eo), an increase in eosinophils is more frequently observed in advanced forms of the disease, i.e. smouldering SM (SSM-eo), aggressive SM (ASM-eo), and mast cell leukemia (MCL-eo).[51], [52] Moreover, eosinophilia in SM is of prognostic significance.52 A subvariant of ASM-eo is lymphadenopathic SM with eosinophilia.[36], [53] In advanced SM and some patients with ISM, eosinophils are considered to belong to

Malignant lymphomas and other lymphoid neoplasms

A number of lymphoid neoplasms may be accompanied by eosinophilia. Such neoplasms include T cell lymphomas, Hodgkin’s disease, and less frequently B cell Non Hodgkin’s lymphomas (NHL), NK cell neoplasms, acute lymphoblastic leukemia (ALL), and other B cell malignancies.[25], [33], [38], [39] In an early phase of disease, eosinophilia may be the only sign for a (T cell) lymphoma. In other patients, a monoclonal T cell population (clone) is detected by PCR or immunophenotyping, but does not

The WHO classification of eosinophil disorders

The WHO classification 2008 defines two groups of patients with neoplastic eosinophils.[60], [61] One group of patients is suffering from a “myeloid or lymphoid (or stem cell) neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB, or FGFR1 genes”.60 The second group, integrated in a subchapter as MPN category, is termed “chronic eosinophilic leukemia, not otherwise specified”.61 The advantage of the WHO classification is that it is based on potential targets, and therefore is in

Therapy of patients with hypereosinophilic disorders

A number of molecular targets related to CEL or to other hematopoietic malignancies presenting with eosinophilia have been defined recently.[25], [38], [39], [40], [41], [42], [43], [44], [62] A summary of potential targets is shown in Table 3. In the individual patient, it is of importance to define the nature of eosinophilia by application of such markers, but also to define the clinical impact of eosinophilia by appropriate staging and assessment of organ infiltration and organ damage, i.e.

Summary and future perspectives

Eosinophilia is an important diagnostic and/or prognostic feature in various myeloid neoplasms. We recommend the use of the appendix ‘eo’ (e.g. MPN-eo, SM-eo) for patients in whom this important diagnostic checkpoint has been reached. Cytogenetic and molecular markers are then applied, and are helpful for determining the final diagnosis. In addition, several of these markers also represent important therapeutic targets. Patients with oncogenic variants of the PDGFR are candidates for treatment

Conflict of interest statement

The author has no conflict of interest.

References (74)

  • A.F. Lopez et al.

    GM-CSF, IL-3 and IL-5: cross-competition on human haemopoietic cells

    Immunol Today

    (1992)
  • K. Sade et al.

    Eosinophilia: a study of 100 hospitalized patients

    Eur J Intern Med

    (2007)
  • T.B. Nutman

    Evaluation and differential diagnosis of marked, persistent eosinophilia

    Immunol Allergy Clin N Am

    (2007)
  • D. Simon et al.

    Eosinophilic disorders

    J Allergy Clin Immunol

    (2007)
  • A.D. Klion et al.

    The hypereosinophilic syndromes working group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

    J Allergy Clin Immunol

    (2006)
  • J. Gotlib et al.

    Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy

    Best Pract Res Clin Haematol

    (2006)
  • P. Valent et al.

    Diagnostic criteria and classification of mastocytosis: a consensus proposal

    Leuk Res

    (2001)
  • B.J. Bain et al.

    Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome

    Immunol Allergy Clin N Am

    (2007)
  • A. Pardanani et al.

    CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy

    Blood

    (2003)
  • A. Pardanani et al.

    Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders

    Blood

    (2003)
  • Y. Yamada et al.

    The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease

    Blood

    (2006)
  • T. Matsushima et al.

    Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia

    Blood

    (2003)
  • A.W. Hauswirth et al.

    A case of smouldering mastocytosis with peripheral blood eosinophilia and lymphadenopathy

    Leuk Res

    (2002)
  • A. Böhm et al.

    Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance

    J Allergy Clin Immunol

    (2007)
  • C. Akin

    Multilineage hematopoietic involvement in systemic mastocytosis

    Leuk Res

    (2003)
  • A. Pardanani et al.

    Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia

    Leuk Res

    (2003)
  • A. Tefferi

    Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment

    Mayo Clin Proc

    (2005)
  • E.H. Stover et al.

    The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo

    Blood

    (2005)
  • C. Baumgartner et al.

    Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRα

    Exp Hematol

    (2008)
  • J. Cools et al.

    PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease

    Cancer Cell

    (2003)
  • E. Lierman et al.

    Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant

    Blood

    (2006)
  • N. von Bubnoff et al.

    The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib)

    Blood

    (2006)
  • J.V. Jovanovic et al.

    Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia

    Blood

    (2007)
  • G.J. Gleich et al.

    The biology of the eosinophilic leukocyte

    Annu Rev Med

    (1993)
  • S.P. Hogan et al.

    Eosinophils: biological properties and role in health and disease

    Clin Exp Allergy

    (2008)
  • J.A. Denburg

    Hemopoietic progenitors and cytokines in allergic inflammation

    Allergy

    (1998)
  • M. Linden et al.

    Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis

    Allergy

    (1999)
  • Cited by (0)

    View full text