Chronic Eosinophilic Leukemia (CEL) (and Other Causes of Hypereosinophilia)

Definition, Etiology, PathogenesisTop

Hypereosinophilia (HE) is defined as particularly high peripheral eosinophil counts (≥1.5×109/L) and/or eosinophilic infiltration of ≥1 target tissue or organ. In the case of target organ damage, hypereosinophilic syndrome (HES) is diagnosed. HE/HES may be nonneoplastic (reactive, congenital, or idiopathic) or neoplastic (clonal; very rare).

1. Primary HE/HES: Conditions with eosinophils present as part of a malignant clone (myeloproliferative neoplasm [MPN], myelodysplastic syndrome [MDS], MDS/MPN overlap syndrome; mastocytosis, myeloid or lymphoid neoplasms associated with eosinophilia and unique molecular rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2).

Chronic eosinophilic leukemia not otherwise specified (CEL-NOS) is a myeloproliferative neoplasm subtype in which uncontrolled clonal proliferation of eosinophil precursors causes hypereosinophilia of peripheral blood with eosinophilic infiltration of bone marrow and other tissues that does not meet criteria for other clonal myeloid diseases with eosinophilia and is negative for other disease-defining mutations.

2. Secondary (reactive) HE/HES: Parasitic infections, allergic reactions including skin and food allergies, allergic and nonallergic asthma, drug-induced (allergic or toxic) reactions. Less commonly pulmonary eosinophilia, graft-versus-host disease, Hodgkin lymphoma, peripheral T-cell lymphomas, Langerhans cell histiocytosis, indolent systemic mastocytosis, solid tumors, allergic bronchopulmonary aspergillosis, chronic inflammatory diseases (eg, inflammatory bowel disease), systemic connective tissue diseases (allergic angiitis and granulomatosis [Churg-Strauss syndrome], other systemic vasculitis syndromes, deep eosinophilic fasciitis with eosinophilia), lymphocyte-variant HES (L-HES) (caused by clonal T-cell cytokine production).

Clinical Features and Natural HistoryTop

1. Symptoms:

1) General symptoms are caused by a massive release of cytokines from eosinophils and include fatigue, fever, sweating, anorexia, and weight loss.

2) Cutaneous symptoms (~60% of patients) include angioedema, erythema, urticaria, subcutaneous papules and nodules, and pruritus. This is very common in L-HES.

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) Gastrointestinal symptoms (~40% of patients) are associated with mucosal ulcerations, bleeding, perforation, cholecystitis, and eosinophilic gastritis/gastroenteritis. They include diarrhea and abdominal pain.

5) Cardiovascular symptoms (~20% of patients) are caused by myocardial and endocardial necrosis and fibrosis, as well as by subendocardial thrombosis. They include valvular regurgitation (most commonly mitral and tricuspid), features of restrictive cardiomyopathy, arrhythmias, conduction disturbances, thromboembolic events, and heart failure.

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 and arthralgia (caused by release of proinflammatory cytokines from eosinophils), and visual disturbances (caused by retinal thrombosis).

2. Natural history: The disease is chronic. 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, in case of CEL, transformation to acute leukemia.

DiagnosisTop

Diagnostic Tests

1. Complete blood count (CBC): Eosinophilia (arbitrarily classified absolute eosinophil counts: mild, 0.5-1.5×109/L; moderate, 1.5-5×109/L; severe, >5×109/L; the average peak eosinophil count in HES is ~6.6×109/L), anemia (~50% of patients), thrombocytopenia (~30%) or thrombocytosis (~15%), monocytosis, and moderate leukocytosis (in particular in patients with CEL).

2. Flow cytometry: Cell markers of peripheral blood or bone marrow can help determine the presence of clonal population and differentiate between primary and secondary HE. Further, an abnormal population of lymphocytes in peripheral blood (eg, CD3+CD4−CD8− or CD3−CD4+CD8+) may suggest L-HES.

3. Bone marrow examination: Aspiration reveals increased proportions of eosinophils, which in some patients are accompanied by dysplasia of megakaryocytes and granulocytes. Trephine biopsy reveals hypercellular marrow, expansion of megakaryopoietic and neutrophil granulocytic lineages, as well as increased amounts of reticulin fibers. Immunophenotyping and immunohistochemical (positive tryptase) studies are also performed. These may include abnormal T-cell receptor rearrangements.

4. Cytogenetic and molecular studies are performed to document clonal expansion (see Diagnostic Criteria, below). These are best performed on bone marrow samples rather than in peripheral blood. In some patients the FIP1L1-PDGFRA fusion gene is found (by polymerase chain reaction [PCR] and by fluorescent in situ hybridization [FISH]). Other cytogenetic parameters could be examined in specialized settings.

5. Other laboratory tests: IgE levels are elevated in patients with idiopathic hypereosinophilia (including the majority of patients with L-HES) and usually normal in patients with CEL-NOS. The activity of granulocyte alkaline phosphatase is increased (leukocyte alkaline phosphatase [LAP] score >100) in patients with CEL-NOS (of note, this is not a serum alkaline phosphate test).

6. Histology: Inflammatory eosinophilic infiltrates are found in biopsy samples of the affected organs.

Diagnostic Criteria

1. CEL-NOS:

1) Eosinophilia ≥1.5×109/L.

2) Absence of the Ph chromosome, absence of the BCR-ABL1 fusion gene, and exclusion of other myeloproliferative (polycythemia vera, essential thrombocytosis, primary myelofibrosis, chronic neutrophilic leukemia) or myelodysplastic-myeloproliferative (chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia) neoplasms.

3) Absence of t(5;12)(q31-35;p13) or other PDGFRB gene rearrangements.

4) Absence of the FIP1L1-PDGFRA fusion gene or other PDGFRA gene rearrangements.

5) Absence of FGFR1 gene rearrangements.

6) Absence of PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion genes.

7) Less than 20% blasts in peripheral blood and bone marrow, absence of inv(16)(p13q22), t(16;16)(p13;q22), or other features that warrant the diagnosis of AML.

8) Presence of a clonal or cytogenetic abnormality, >2% blasts in peripheral blood, or >5% blasts in bone marrow.

2. Neoplasms with a PDGFRA gene rearrangement:

1) A myeloid (most frequently CEL, less often AML) or less commonly lymphoid (T-lymphoblastic lymphoma) neoplasm with significant eosinophilia.

2) Presence of the FIP1L1-PDGFRA fusion gene.

Differential Diagnosis

Disorders of the organs affected in HES (see Clinical Features, above).

TreatmentTop

1. Patients with eosinophil counts <5000/microL and no organ involvement: Cytoreduction is not necessary.

2. HE with the FIP1L1-PDGFRA or PDGFRB gene: Imatinib. Patients with cardiac involvement should receive concomitant glucocorticoids when therapy with imatinib is initiated to prevent acute cardiac injury.

3. HES with FGFR1 rearrangement: Given the aggressive course of the disease, intensive chemotherapy is used followed by stem cell transplant.

4. HES without PDGFRA, PDGFRB, or FGFR1 rearrangement: Glucocorticoids, for instance, prednisone 1 mg/kg until eosinophil counts decrease <1.5×109/L and symptom control is achieved; then slowly taper the dose. Patients at risk for infection with Strongyloides as a cause of HES should receive ivermectin (200 microg/kg/d for 2 days) concomitantly with glucocorticoids to avoid dissemination of infection. Monoclonal antibodies against interleukin 5 (IL-5) (mepolizumab and benralizumab) are safe and effective in reducing blood and tissue eosinophil counts, improving clinical outcomes, and helping to reduce the dose of maintenance glucocorticoids.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Roufosse F, Kahn JE, Rothenberg ME, et al; HES Mepolizumab study group. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020 Dec;146(6):1397-1405. doi: 10.1016/j.jaci.2020.08.037. Epub 2020 Sep 18. PMID: 32956756; PMCID: PMC9579892. Kuang FL, Legrand F, Makiya M, et al. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. N Engl J Med. 2019 Apr 4;380(14):1336-1346. doi: 10.1056/NEJMoa1812185. PubMed PMID: 30943337; PubMed Central PMCID: PMC6557265. Rothenberg ME, Klion AD, Roufosse FE, et al; Mepolizumab HES Study Group. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008 Mar 20;358(12):1215-28. doi: 10.1056/NEJMoa070812. Epub 2008 Mar 16. Erratum in: N Engl J Med. 2008 Jun 5;358(23): 2530. PubMed PMID: 18344568. Roufosse FE, Kahn JE, Gleich GJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013 Feb;131(2):461-7.e1-5. doi: 10.1016/j.jaci.2012.07.055. Epub 2012 Oct 4. PubMed PMID: 23040887; PubMed Central PMCID: PMC3558744.

5. CEL-NOS and patients not responding to treatment: Cytotoxic agents (hydroxyurea [INN hydroxycarbamide]; if ineffective, interferon alpha, then vincristine or etoposide). In patients with no response to these agents consider less established treatments (mepolizumab, alemtuzumab)Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Kuang FL, Fay MP, Ware J, et al. Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome. J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1518-1527.e5. doi: 10.1016/j.jaip.2018.04.033. Epub 2018 May 8. PubMed PMID: 29751154; PubMed Central PMCID: PMC6173586. or consider allogeneic hematopoietic stem cell transplant. Rarely leukapheresis may be considered.

Follow-UpTop

CBC (target eosinophil counts <1.5×109/L); other studies relevant to organ involvement (including echocardiography) every 6 to 12 months. In patients with the FIP1L1-PDGFRA gene, perform molecular studies every 3 months if indicated to monitor response to therapy or to determine if remission is durable in patients who have achieved a complete molecular response.

PrognosisTop

The majority of patients with HES have a good response to glucocorticoids in monotherapy and in combination with hydroxyurea. Patients who are refractory to these treatments respond to other modalities listed above (5-year survival rates are up to 90%). Over 90% of patients with the FIP1L1-PDGFRA gene respond to imatinib. In the case of CEL-NOS, the prognosis is poor; in half of these patients, transformation to AML occurs and the mean survival is 22 months.