Eosinophilia is the hallmark of CEL and other hematologic disorders, and increased eosinophil counts may be detected incidentally. Routine analyses of blood may simultaneously reveal neutrophilia or basophilia, anemia, thrombocytopenia or thrombocytosis [3].

CEL is associated with progressive end-organ damage and patients may present with a variety of general and local symptoms. With regards to the former, patients may claim fatigue and weakness, and sometimes they suffer from fever. Virtually all tissues depend on blood supply and are thus susceptible to infiltration with eosinophils, most commonly resulting in dermatological, pulmonary and gastrointestinal symptoms:

• Angioedema, rash, pruritus
• Rhinitis, cough, dyspnea, possibly due to pulmonary fibrosis
• Gastritis, enteritis, diarrhea
• Endocardial damage, thromboembolism
• Progressive heart failure, myalgia
• Encephalopathy

The broad spectrum of end-organ manifestations of eosinophilia has been reviewed elsewhere [11].

As per definition, CEL is a primary, clonal disorder. Thus, thorough anamnesis and physical examination should be conducted to identify possible triggers of secondary eosinophilia. The latter may be induced by hypersensitivity reactions, infestation with parasites, autoimmune disorders, psoriasis and other skin diseases, among others. These are not necessarily associated with severe clinical symptoms, and if patients are unaware of their condition and don't seek medical attention, they may develop chronic eosinophilia.

In case of confirmed primary eosinophilia, blood smears should be prepared because they may reveal important morphological features of distinct cell populations. Results may or may not hint at a malignancy, and they may allow for the distinction of myeloid and lymphoid neoplasms and myelodysplastic syndromes.

FIP1L1-PDGFRA fusion has been reported to be the most common chromosomal rearrangement causing CEL [10]. Consequently, patients suspicious of CEL should first be tested to this effect. Nested reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization may be applied to demonstrate the absence of loci physiologically located between those genes encoding for FIP1L1 and PDGFRA. A combined approach may significantly increase the sensitivity of tests. Blood and bone marrow specimens that test negative for FIP1L1-PDGFRA should subsequently be subjected to analysis for PDGFRB or FGFR1 rearrangements.

According to the diagnostic guidelines given by the World Health Organization, identification of any of the aforementioned cytogenetic anomalies warrants the diagnosis of an eosinophilic myeloproliferative disorder due to rearrangements of PDGFRA, PDGFRB or FGFR1 [2]. However, CEL-NOS is not associated with any of those abnormalities, and other myeloid malignancies should be ruled by the following measures:

• Demonstration of clonality of eosinophils.
• Screens for chromosomal and genetic anomalies known to be involved in the pathogenesis of chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, e.g., Philadelphia chromosome, somatic mutations of the gene encoding cytoplasmic Janus kinase 2 or the thrombopoietin receptor.
• Ascertainment of blast cell ratios in blood and bone marrow. In case of CEL-NOS, they do exceed 2% and 5%, respectively, but are lower than 20%. Even higher blast counts may indicate acute myeloid leukemia.

If these criteria are not met by a patient presenting with chronic eosinophilia, they are usually diagnosed with IHS.

Patients developing CEL due to rearrangements involving those genes encoding for PDGFRA or PDGFRB generally respond well to treatment with imatinib. Application of 100 mg imatinib per day has been shown to induce complete remission, and recurrence is avoided by long-term administration of that same dose once a week. Slightly higher doses of imatinib have also been applied [4]. The necessity for maintenance therapy is not completely clear because some patients who discontinued use of imatinib experienced relapses while others did not [10]. Of note, some patients presenting with PDGFRA or PDGFRB anomalies may be or become resistant to imatinib therapy. This may be due to an additional, acquired mutation of the respective fusion gene [12].

Although considerable research efforts have been made to identify additional compounds that may be of use in CEL patients, so far, other tyrosine kinase inhibitors have only been used anecdotally to treat this myeloproliferative disease. Accordingly, treatment options for patients resistant to imatinib therapy are reduced to those available for IHS: Remediation of eosinophilia may be achieved by administration of immunosuppressive drugs like corticosteroids or interferon-α. Moreover, hydroxyurea may be applied in combination with immunosuppressants or as monotherapy in patients who either don't respond or don't tolerate other therapeutic regimens [2].

Allogeneic stem cell transplantation should be considered in cases of advanced CEL and poor response to drug therapy.

The outcome depends on the patient's responsiveness to treatment, and the latter varies depending on the underlying genetic aberration. Patients diagnosed with PDGFRA or PDGFRB rearrangements generally respond well to imatinib therapy, and their prognosis is very good [10]. In contrast, effective drugs are not yet available to treat FGFR1-related CEL or CEL-NOS, and the outcome is considerably worse. Median survival times are below two years.

CEL is a myeloproliferative disorder that may be associated with determined anomalies of PDGFRA, PDGFRB or FGFR1. Some patients show neither of such rearrangements and may consequently be diagnosed with CEL-NOS [2]. Distinction between those subtypes of CEL is of utmost importance for the choice of therapy since patients suffering from leukemia due to sequence alterations involving genes encoding for PDGFRA or PDGFRB respond to imatinib.

In detail, the following chromosomal and genetic anomalies have been associated to CEL:

• An interstitial deletion on the long arm of chromosome 4 fuses those genes encoding for FIP1-like 1 protein (FIP1L1) and PDGFRA, thus yielding the respective FIP1L1-PDGFRA protein, a constitutively active tyrosine kinase [3]. In fact, this tyrosine kinase is the molecular target of imatinib.
• Rearrangements affecting the long arm of chromosome 5 and the gene encoding for PDGFRB are more heterogenous, but generally respond to imatinib treatment as well [4].
• Similarly, distinct chromosomal translocations affecting the short arm of chromosome 8 may yield fusion proteins comprising FGFR1 [5]. Although these anomalies may cause alterations of tyrosine kinase activity - FGFR1 is indeed a tyrosine kinase receptor -, effective treatments for this form of CEL are still lacking.
• According to current knowledge, CEL-NOS is diagnosed in CEL patients who have proven negative for either of the aforementioned rearrangements. Presumably, there are several, as of yet unknown genetic aberrations that may induce CEL. It is to be expected that they are identified over the course of time, and current classifications of eosinophilic myeloproliferative disorders will have to be revised accordingly [6].

Little is known about environmental factors provoking the aforedescribed conditions. Previous exposure to radiation has only been reported in isolated cases [7].

The overall annual incidence of CEL and IHS has been estimated to be 0.036 per 100,000 inhabitants [8]. While a racial predilection has not yet been reported, according to some studies, males are affected slightly more often than females. CEL is typically diagnosed in adults, with an age peak during the fourth to sixth decade of life.

As has been indicated above, certain subtypes of CEL are associated with genetic anomalies provoking constitutive activity of tyrosine kinases. The respective rearrangements of PDGFRA, PDGFRB or FGFR1 have not only been detected in eosinophils, but also in non-eosinophilic granulocytes, monocytes and mast cells [9], and this observation implies that chromosomal alterations originate from common precursor cells, i.e., from myeloblasts or earlier developmental stages of myeloid cells. Some CEL patients also present with monocytosis or mastocytosis, and co-occurence of these conditions may indicate genetic aberrations in early precursors. Still, despite the knowledge about growth factors regulating growth, division and survival of cells, it remains unknown why the affected tyrosine kinases preferentially induce an uncontrolled proliferation of eosinophilic precursors. The fact that administration of tyrosine kinase inhibitors like imatinib may induce complete hematologic and molecular remission illustrates the pathogenic importance of the aforementioned rearrangements [10].

Pathogenetic events causing manifest CEL-NOS are even less well understood. Recently, EBV6-ACSL6 rearrangement has been observed in a patient diagnosed with CEL-NOS [6]. EBV6 is an oncogene which has previously been related to leukemia and non-hematologic neoplasms; ACSL6 encodes for acyl-CoA synthetase long-chain family member 6. It is still unclear how dysfunction of an enzyme involved in fatty acid metabolism may cause CEL.

Since specific triggers for causative genetic aberrations have not yet been identified, no specific measures can be recommended to prevent CEL.

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative disorder. The hallmark of CEL are peripheral blood eosinophil counts exceeding 1.5 * 10^9 per liter, but this finding is not specific for CEL. Indeed, it often is a diagnostic challenge to distinguish CEL from idiopathic hypereosinophilic syndrome (IHS), a disease characterized by eosinophilia persisting for more than six months [1]. In this context, the World Health Organization has recently published revised definitions and diagnostic guidelines for eosinophilic disorders [2]. The respective publication describes, but is not limited to, the following neoplasms:

• Myeloid neoplasm with eosinophilia and rearrangement of platelet-derived growth factor receptor-α (PDGFRA)
• Myeloid neoplasm with eosinophilia and rearrangement of platelet-derived growth factor receptor-β (PDGFRB)
• Myeloid neoplasm with eosinophilia and rearrangement of fibroblast growth factor receptor 1 (FGFR1)
• Chronic eosinophilic leukemia, not otherwise specified (NOS)

Of note, IHS is not considered a myeloid malignancy. As its name implies, IHS is an idiopathic disease diagnosed after exclusion of known forms of primary and secondary eosinophilia.

CEL may be provoked by genetic aberrations that form the basis for the above given classification, but some patients present neither of those chromosomal anomalies that have been related to the disease so far. In any case, the precise trigger of malignant transformation remains unknown. Clonal proliferation of precursors of eosinophil granulocytes leads to increased eosinophil counts in bone marrow, peripheral blood and end organs, whereby the latter may provoke potentially life-threatening organ failure. Most CEL patients eventually develop dermatological, pulmonary and/or gastrointestinal symptoms [2], but the most severe complication of CEL is cardiac involvement. In case of IHS, this condition is referred to as Loeffler endocarditis; it may result in heart failure and death. In case of CEL associated with rearrangements of PDGFRA or PDGFRB, application of tyrosine kinase inhibitor imatinib significantly improves survival. Therapeutic options for patients suffering from resistant forms of CEL are more restricted, though.

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative disorder. Here, the medical term myeloproliferative refers to the formation of certain blood cells in the bone marrow. Hematopoietic stem cells differentiate into myeloid precursors, myeloblasts, several intermediate developmental stages, and finally into red blood cells, neutrophils, eosinophils, basophils, mast cells and monocytes. Under physiological conditions, eosinophils only account for minor shares of white blood cells; they fulfill important functions in combating parasites and other pathogens.

In patients suffering from CEL, eosinophil counts are largely increased. This condition may be induced by determined chromosomal rearrangements. These may provoke receptors involved in the regulation of growth, division and survival of blood cells to become constitutively active, i.e., to escape from higher-level regulatory mechanisms. Although eosinophils are formed in the bone marrow, they subsequently circulate through the whole body and may thus reach any tissue. Infiltration of eosinophils primarily causes dermatological, pulmonary and gastrointestinal symptoms, e.g., rash, rhinitis, cough, breathing difficulties, and abdominal pain. However, these cells may also interfere with cardiac and brain function, and such complications worsen the outcome.

As has been indicated above, malfunction of distinct receptors triggers CEL. Some of those receptors can be inhibited by a compound named imatinib, and patients diagnosed with the respective subtypes of CEL may achieve complete remission. Other affected individuals require immunosuppressive therapy to avoid end-organ damage by infiltrating eosinophils.

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