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Chronic Eosinophilic Leukemia

Chronic eosinophilic leukemia is a rare myeloid malignancy characterized by primary eosinophilia and progressive organ damage. Diagnosis of this disease and distinction from idiopathic hypereosinophilic syndrome requires the detection of determined mutations, demonstration of clonality of eosinophils, or observation of increased ratios of eosinophilic precursors in bone marrow or blood.

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Presentation

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:

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

Splenomegaly
  • We present a 24-year-old-male with left lower quadrant abdominal pain, elevated eosinophil counts and splenomegaly. Molecular analysis was positive for FIP1LI -PDGFRA gene compatible with chronic eosinophilic leukemia.[ncbi.nlm.nih.gov]
  • The only clues for the diagnosis of leukemia were splenomegaly and high serum vitamin B12, most of which was bound to transcobalamin I. The latter finding presents a useful diagnostic criterium in myeloproliferative disorders.[ncbi.nlm.nih.gov]
  • Splenomegaly was constant in FIP1L1-PDGFRA positive CEL but not in the other HES patients (only 1/3).[ncbi.nlm.nih.gov]
  • Cardiac symptoms are also possible. [1] In cases associated with PDGFRB and FGFR1 mutations, splenomegaly is common.[en.wikipedia.org]
  • The only clues for the diagnosis of leukemia were splenomegaly and high serum vitamin B 12, most of which was bound to transcobalamin I. The latter finding presents a useful diagnostic criterium in myeloproliferative disorders. 1975 S.[karger.com]
Fever
  • Abstract A 5-year-old girl was admitted to our hospital due to fatigue and fever lasting for six months. She had systolic murmur in the mesocardiac and apex regions and hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • Signs and symptoms of chronic eosinophilic leukemia include fever and feeling very tired. Chronic eosinophilic leukemia may not cause early signs or symptoms. It may be found during a routine blood test.[navigatingcare.com]
  • Signs and symptoms [ edit ] Signs and symptoms may include weight loss, fever, malaise, cough, skin and mucosal lesions, diarrhea, and peripheral neuropathy.[en.wikipedia.org]
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • See your doctor if you have these symptoms: tiredness fever cough muscle pain itching diarrhea swelling under the skin around the eyes and lips, in the throat or on the hands and feet Diagnosis Diagnosing chronic eosinophilic leukemia usually begins with[cancer.ca]
Anemia
  • Abstract We report a case of chronic eosinophilic leukemia in a 9 year old girl who presented with anemia, thrombocytopenia, leucocytosis (mostly dysplastic eosinophils), lymphadenopathy and hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • We describe a case of chronic eosinophilic leukemia (CEL) in a 72-year-old male with a history of previously treated non-Hodgkin's lymphoma (NHL) presenting with erythrophagocytosis by eosinophils and an associated autoimmune hemolytic anemia (AIHA).[ncbi.nlm.nih.gov]
  • The FIP1L1-PDGFRalpha-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time.[ncbi.nlm.nih.gov]
  • CASE REPORT: A 53-year-old male presented an absolute eosinophil count of 25,000/mm(3), anemia (Hb 10.2 g/dl) and a moderate increase in the platelet count (571,000/mm(3)).[ncbi.nlm.nih.gov]
  • Systemic examination was normal, except for anemia.[ingentaconnect.com]
Fatigue
  • Abstract A 5-year-old girl was admitted to our hospital due to fatigue and fever lasting for six months. She had systolic murmur in the mesocardiac and apex regions and hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues.[clinicaladvisor.com]
  • Symptoms : 1) General symptoms are caused by a massive release of cytokines from eosinophils and include fatigue, fever, sweating, anorexia, and weight loss. 2) Cardiovascular symptoms (observed in 20% of patients) are caused by myocardial and endocardial[empendium.com]
Weakness
  • Signs that you have one of these disorders include: Anemia (you don’t have enough red blood cells to carry oxygen) Shortness of breath Pale skin Weakness and fatigue Lack of appetite Bleeding in excess (even when you get a minor cut) Sinus infections[webmd.com]
  • With regards to the former, patients may claim fatigue and weakness, and sometimes they suffer from fever.[symptoma.com]
Cough
  • Signs and symptoms [ edit ] Signs and symptoms may include weight loss, fever, malaise, cough, skin and mucosal lesions, diarrhea, and peripheral neuropathy.[en.wikipedia.org]
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • See your doctor if you have these symptoms: tiredness fever cough muscle pain itching diarrhea swelling under the skin around the eyes and lips, in the throat or on the hands and feet Diagnosis Diagnosing chronic eosinophilic leukemia usually begins with[cancer.ca]
  • Cough. Swelling under the skin around the eyes and lips, in the throat, or on the hands and feet. Muscle pain. Itching. Diarrhea. This information is not intended to replace the advice of a doctor.[navigatingcare.com]
  • Infiltration of eosinophils primarily causes dermatological, pulmonary and gastrointestinal symptoms, e.g., rash, rhinitis, cough, breathing difficulties, and abdominal pain.[symptoma.com]
Dyspnea
  • We report a case of a 45-year-old African-American male with hepatitis C and sustained peripheral blood eosinophilia who presented with gross hematuria, dyspnea on exertion, chills, decreased appetite and weight loss of 40 pounds associated with hepatosplenomegaly[ncbi.nlm.nih.gov]
  • A case of idiopathic hypereosinophilic syndrome presenting with nocturia and dyspnea. Korean J Asthma Allergy Clin Immunol 2010;30:241–245. 3. Kim DW, Shin MG, Yun HK, et al.[synapse.koreamed.org]
  • A 28-year-old man presented to the emergency department with a headache, dyspnea, and aphasia. Acute infarction in the left posterior middle cerebral artery territory was found on brain magnetic resonance imaging.[kjim.org]
  • […] conduction disturbances, thromboembolic events, and heart failure. 3) Respiratory symptoms ( 50% of patients) are caused by eosinophilic infiltrates, pulmonary fibrosis, heart failure, or pulmonary embolism and include chronic nonproductive cough and dyspnea[empendium.com]
  • 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[symptoma.com]
Rhinitis
  • Infiltration of eosinophils primarily causes dermatological, pulmonary and gastrointestinal symptoms, e.g., rash, rhinitis, cough, breathing difficulties, and abdominal pain.[symptoma.com]
Diarrhea
  • Signs and symptoms [ edit ] Signs and symptoms may include weight loss, fever, malaise, cough, skin and mucosal lesions, diarrhea, and peripheral neuropathy.[en.wikipedia.org]
  • See your doctor if you have these symptoms: tiredness fever cough muscle pain itching diarrhea swelling under the skin around the eyes and lips, in the throat or on the hands and feet Diagnosis Diagnosing chronic eosinophilic leukemia usually begins with[cancer.ca]
  • Diarrhea. This information is not intended to replace the advice of a doctor. Navigating Care disclaims any liability for the decisions you make based on this information.[navigatingcare.com]
  • Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues.[clinicaladvisor.com]
  • […] erythema, urticaria, subcutaneous papules and nodules, and pruritus. 5) Gastrointestinal symptoms ( 30% of patients) are associated with mucosal ulcerations, bleeding, perforation, cholecystitis, and eosinophilic gastritis/gastroenteritis; they include diarrhea[empendium.com]
Heart Failure
  • On admission, the patient had left heart failure accompanied by a large thrombus in the left ventricle. After pretreatment with furosemide and prednisolone, we started imatinib treatment at 100 mg/day.[ncbi.nlm.nih.gov]
  • In some cases, the course may be mild, but most frequently it is progressive and may rapidly lead to death due to organ involvement (usually heart failure) or transformation to acute leukemia. Diagnosis Top Diagnostic Tests 1.[empendium.com]
  • Symptoms are similar to those mentioned previously for all myeloproliferative neoplasms, but may also include: Central nervous system irregularities Congestive heart failure Pulmonary fibrosis Peripheral vasculitis Gangrene Heart/lung damage from eosinophilic[labce.com]
  • In case of IHS, this condition is referred to as Loeffler endocarditis; it may result in heart failure and death.[symptoma.com]
  • Heart failure, respiratory distress, central nervous system manifestations, and fever were characteristic symptoms. Hepatosplenomegaly was found in 31 patients and lymphadenopathy in 26 patients.[annals.org]
Systolic Murmur
  • She had systolic murmur in the mesocardiac and apex regions and hepatosplenomegaly. Laboratory evaluation revealed leukocyte and eosinophil counts of 176 and 144.32 x 10(9)/L, 3.4% blasts in bone marrow and monosomy 8.[ncbi.nlm.nih.gov]
Myalgia
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues.[clinicaladvisor.com]
  • ; they include diarrhea and abdominal pain. 6) Neurologic symptoms ( 55% of patients) include behavioral abnormalities, memory impairment, ataxia, and features of peripheral polyneuropathy. 7) Other symptoms include hepatomegaly and/or splenomegaly, myalgia[empendium.com]
  • […] 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[symptoma.com]
  • […] reaction, parasitic infection or connective disease) Eosinophil count can vary from 1.5 - 400 x 10 9 /L Can have leukocytosis (20 - 30 x 10 9 /L), anemia, thrombocytopenia or thrombocytosis Symptoms: weight loss, night sweats, fever (12%), fatigue (26%), myalgias[pathologyoutlines.com]
Pruritus
  • The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %).[ncbi.nlm.nih.gov]
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues.[clinicaladvisor.com]
  • Pruritus and skin rash can occur as a result of eosinophilia but this finding is not specific.[pathologyoutlines.com]
  • […] eosinophilic infiltrates, pulmonary fibrosis, heart failure, or pulmonary embolism and include chronic nonproductive cough and dyspnea. 4) Cutaneous symptoms ( 60% of patients) include angioedema, erythema, urticaria, subcutaneous papules and nodules, and pruritus[empendium.com]
Angioedema
  • Chronic Eosinophilic Leukemia (CEL) Clinical signs fever fatigue cough angioedema myalgia pruritus, diarrhoea sometimes neurological, pulmonar an rheumatic symptoms Etiology The BCR-ABL1 gene or the PDGFRA, PDGFRB rebuild is absent.[atlases.muni.cz]
  • Patients can present with fever, fatigue, cough, diarrhea, myalgias, pruritus, or angioedema reflecting activation and degranulation of the aberrant eosinophils in the lungs, GI tract, muscles, skin, or mucosal tissues.[clinicaladvisor.com]
  • […] failure. 3) Respiratory symptoms ( 50% of patients) are caused by eosinophilic infiltrates, pulmonary fibrosis, heart failure, or pulmonary embolism and include chronic nonproductive cough and dyspnea. 4) Cutaneous symptoms ( 60% of patients) include angioedema[empendium.com]
  • 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[symptoma.com]
  • […] parasitic infection or connective disease) Eosinophil count can vary from 1.5 - 400 x 10 9 /L Can have leukocytosis (20 - 30 x 10 9 /L), anemia, thrombocytopenia or thrombocytosis Symptoms: weight loss, night sweats, fever (12%), fatigue (26%), myalgias or angioedema[pathologyoutlines.com]
Eruptions
  • Generalized eruptive histiocytosis in association with a myeloid neoplasm may occur in 2 variants: a reactive condition or a clonal derivative of the underlying leukemia.[ncbi.nlm.nih.gov]
  • A 37-year-old male presented with severe oral and genital mucosal ulcers, lichenoid eruption and twenty-nail dystrophy. Systemic examination was normal, except for anemia.[ingentaconnect.com]
Encephalopathy
  • […] 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[symptoma.com]

Workup

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.

Thrombocytosis
  • […] hematologic disorder with a reactive eosinophilia (T cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, ALL, mastocytosis) (3) acute myeloid leukemia (AML) (4) myelodysplastic disorders (5) other myeloproliferative disorders (polycythemia, primary thrombocytosis[meducator3.net]
  • CEL-NOS : 1) Eosinophilia 1500/microL. 2) Absence of the Ph chromosome, BCRABL1 fusion gene, and exclusion of other myeloproliferative (polycythemia vera, essential thrombocytosis, primary myelofibrosis) or myelodysplastic-myeloproliferative (chronic[empendium.com]
  • Routine analyses of blood may simultaneously reveal neutrophilia or basophilia, anemia, thrombocytopenia or thrombocytosis. CEL is associated with progressive end-organ damage and patients may present with a variety of general and local symptoms.[symptoma.com]
  • […] longstanding eosinophilia without specific etiology (i.e. no allergy, asthma, drug reaction, parasitic infection or connective disease) Eosinophil count can vary from 1.5 - 400 x 10 9 /L Can have leukocytosis (20 - 30 x 10 9 /L), anemia, thrombocytopenia or thrombocytosis[pathologyoutlines.com]
  • […] response to tyrosine kinase inhibitor (TKI) therapy Haematological/cytogenetic criteria Persistent or increasing high white blood cell count ( 10 x 109/L), unresponsive to therapy Persistent or increasing splenomegaly, unresponsive to therapy Persistent thrombocytosis[en.wikipedia.org]
Lymphocytopenia
  • The most common grade 3/4 hematologic laboratory abnormalities were lymphocytopenia (31.3 %) and neutropenia (25.0 %). The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %).[ncbi.nlm.nih.gov]
Lymphocytic Infiltrate
  • A liver biopsy revealed hepatocyte necrosis with lymphocyte infiltration. Fortunately, the FIP1L1-PDGFRA fusion transcript had become undetectable, and imatinib treatment was stopped. The liver dysfunction resolved within a month.[ncbi.nlm.nih.gov]
Liver Biopsy
  • A liver biopsy revealed hepatocyte necrosis with lymphocyte infiltration. Fortunately, the FIP1L1-PDGFRA fusion transcript had become undetectable, and imatinib treatment was stopped. The liver dysfunction resolved within a month.[ncbi.nlm.nih.gov]

Treatment

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.

Prognosis

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.

Etiology

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].

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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

Summary

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.

Patient Information

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.

References

Article

  1. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010; 85(2):158-164.
  2. Gotlib J. World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015; 90(11):1077-1089.
  3. Gotlib J, Cools J, Malone JM, 3rd, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004; 103(8):2879-2891.
  4. Falchi L, Verstovsek S. Eosinophilia in Hematologic Disorders. Immunol Allergy Clin North Am. 2015; 35(3):439-452.
  5. Bain BJ. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1. Haematologica. 2010; 95(5):696-698.
  6. Su RJ, Jonas BA, Welborn J, Gregg JP, Chen M. Chronic eosinophilic leukemia, NOS with t(5;12)(q31;p13)/ETV6-ACSL6 gene fusion: a novel variant of myeloid proliferative neoplasm with eosinophilia. Hum Pathol (N Y). 2016; 5:6-9.
  7. Balatzenko G, Stoyanov N, Bekrieva E, Guenova M. Chronic eosinophilic leukemia with FIP1L1-PDGFRA transcripts after occupational and therapeutic exposure to radiation. Hematol Rep. 2011; 3(2):e17.
  8. Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol. 2010; 126(1):179-181.
  9. Yamada Y, Rothenberg ME, Cancelas JA. Current concepts on the pathogenesis of the hypereosinophilic syndrome/chronic eosinophilic leukemia. Transl Oncogenomics. 2006; 1:53-63.
  10. Qu SQ, Qin TJ, Xu ZF, et al. Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in china. Oncotarget. 2016.
  11. Nutman TB. Evaluation and differential diagnosis of marked, persistent eosinophilia. Immunol Allergy Clin North Am. 2007; 27(3):529-549.
  12. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003; 348(13):1201-1214.

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Last updated: 2018-06-21 19:24