Chronic Eosinophilic Leukemia

Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Patients present with constitutional symptoms along with signs and symptoms of anemia and thrombocytopenia. Studies show absolute eosinophilic count ≥ 1.5 x 10⁹/L, with bone marrow blasts (5%–19%). Evidence of clonal abnormality or elevated blasts are needed; without either, idiopathic HES is the appropriate diagnosis. Nevertheless, both have a similar treatment approach. Management aims to reduce the burden of hypercellularity to prevent end-organ damage. Treatment options include corticosteroids, chemotherapeutic agents, and interferon-α.

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Overview

Definition

Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is a rare chronic myeloproliferative neoplasm typified by clonal eosinophilic expansion in the bone marrow with increased blasts (< 20%).

Classifying CEL, NOS

Based on eosinophilias:

  • Hypereosinophilia: absolute eosinophilic count of ≥ 1.5 x 10⁹/L
  • Hypereosinophilic syndrome (HES): hypereosinophilia with associated organ damage
    • HES myeloid variants:
      • CEL, NOS: hypereosinophilia with proven clonal abnormality or myeloblast excess
      • Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1, or with PCM1-JAK2
    • Idiopathic HES is the appropriate term if HES has:
      • No proven clonality or not associated with elevated blasts
      • No secondary causes
    • Other clinically relevant variants (e.g., lymphocytic variants, familial variants)

CEL, NOS is classified under chronic myeloproliferative neoplasms (WHO classification):

  • CML
  • Polycythemia vera (PCV)
  • Primary myelofibrosis (PMF)
  • Essential thrombocythemia (ET)
  • Chronic neutrophilic leukemia (CNL)
  • CEL, NOS
  • Myeloproliferative neoplasm, unclassified

Epidemiology and etiology

  • Rare condition
  • Because of the difficulty of proving clonality or distinguishing CEL, NOS from idiopathic HES, exact prevalence is unknown.
  • In about 10% of patients, eosinophilia is noted incidentally.
  • Limited data suggest male predilection.

Pathophysiology

Hematopoiesis

Hematopoiesis starts with a hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Lymphoid stem cell: gives rise to lymphocytes
  • Myeloid stem cell: eventually differentiates into platelets, erythrocytes, granulocytes (neutrophils, basophils, eosinophils), and monocytes
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells.
    • Granulocyte-macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes (platelets)
    • Erythropoietin (EPO) → differentiation to erythrocytes (RBCs)
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Eosinophilia

  • Overproduction of eosinophils in bone marrow in CEL, NOS occurs but the underlying mechanism that facilitates this process is not clear.
  • Other variants associated with HES have chromosomal aberrations (e.g., PDGFRA fusion with other genes, rearrangements involving PDGFRB).
  • Theoretically, enhanced activity or defective regulation of eosinophil synthesis ia suspected.
  • With ↑ eosinophils, organ infiltration follows → enhanced fibrosis → tissue and organ damage and dysfunction

Clinical Presentation

  • Insidious onset
  • Constitutional symptoms (fever, weight loss, night sweats)
  • Symptoms related to:
    • Anemia: fatigue, palpitations
    • Thrombocytopenia: bruising, petechiae 
  • Hepatosplenomegaly
  • Can have overlapping symptoms (associated with eosinophilic activation): 
    • Angioedema
    • Dermatologic: cutaneous lesions, rashes
    • Pulmonary/respiratory: cough, asthma
    • GI: gastroenteritis/diarrhea
    • Rheumatologic: vasculitis, arthralgia
    • Cardiac: 
      • Cardiomegaly, cardiomyopathy (endomyocardial fibrosis is most serious complication)
      • Cardiac involvement is unpredictable (not correlated to level of eosinophilia).
      • Found also in a different variant with FIP1L1-PDGFRA fusion
    • Neurologic: neuropathy, memory loss

Diagnosis

Diagnosis

Chronic eosinophilic leukemia, not otherwise specified is a diagnosis of exclusion (requires ruling out other eosinophilic conditions) and is defined according to the WHO diagnostic criteria:

  • Meets the following criteria:
    • Eosinophil count: absolute eosinophilic count ≥ 1.5 x 10⁹/L
    • Peripheral blood blast count: > 2% 
    • Bone marrow blast cell count: 5%–19% of all nucleated cells
    • Evidence of clonality:
      • Detection of clonal cytogenetic abnormality OR
      • By demonstration of a very skewed expression of X chromosome genes
  • Does not meet the WHO diagnostic criteria for:
    • Other myeloproliferative neoplasms:
      • CML
      • PCV
      • ET
      • PMF
      • CNL
    • inv(16)(p13q22) or t(16;16)(p13;q22)
    • Myelodysplastic syndrome/myeloproliferative neoplasm (chronic myelomonocytic leukemia or atypical CML)
    • Lymphocytic variant of hypereosinophilia 
  • No rearrangement of PDGFRA, PDGFRB, FGFR1, or with PCM1-JAK2
Approach to hypereosinophilia

Approach to hypereosinophilia

Image by Lecturio.

Tests

  • Laboratory features found in CEL, NOS (which are also found in other myeloid variants):
    • CBC and peripheral blood smear: 
      • Eosinophils: absolute eosinophilic count ≥ 1.5 x 10⁹/L
      • Anemia
      • Thrombocytopenia
      • Circulating leukocyte precursors
    • Serum vitamin B12 (elevated)
    • Bone marrow biopsy: hypercellular marrow with markedly increased eosinophil precursors and eosinophils (orderly maturation)
  • Check studies for chromosomal or gene abnormalities to rule out other disorders:
    • BCR-ABL/Philadelphia chromosome
    • PDGFRA 
    • PDGFRB
    • PCM1-JAK2 
    • FGFR1
  • Assess end-organ involvement depending on presentation:
    • Metabolic panel
    • Liver profile
    • Echocardiogram
    • Imaging:
      • Echocardiogram
      • Chest X-ray/CT
      • Abdominal CT
Activated eosinophils in hypereosinophilic syndrome

Activated eosinophils in the peripheral blood of a patient with hypereosinophilic syndrome showing cytoplasmic clearing, nuclear dysplasia, and the presence of immature forms

Image: “Activated Eosinophils in Idiopathic Hypereosinophilic Syndrome (9125007255)” by NIAID. License: CC BY 2.0

Management

  • Goals of therapy:
    • Reduction of absolute eosinophil count (AEC): maintain below 1,500 cells/μL (to prevent end-organ damage)
    • Improvement of signs and symptoms
    • Prevention of disease progression
  • CEL, NOS clinical course:
    • Course is variable.
    • Transformation to acute leukemia seen
  • Treatment:
    • Due to rarity and variability in the course of disease, optimal treatment is not clear.
    • Initial approach: corticosteroids (1st-line therapy, as with idiopathic HES)
    • Steroid-refractory cases:
      • Chemotherapeutic agents: hydroxyurea, cyclophosphamide, vincristine
      • Interferon-α
    • Some patients may benefit from a trial of imatinib, a tyrosine kinase inhibitor (which is effective for PDGFRA-positive HES variants).
    • Other therapies that have shown some efficacy:
      • Anti-IL-5 (mepolizumab) 
      • Anti-CD52 (alemtuzumab) 

Differential Diagnosis

Other eosinophilias

  • Secondary eosinophilia: a cytokine-derived (IL-5) reactive phenomenon. Worldwide, parasitic diseases are the predominant cause, but in developed countries, allergic diseases are the most common etiology. Signs and symptoms are constitutional and end-organ-involvement presentations can be seen. Diagnostic tests are CBC with differential, blood chemistries, and potential bone marrow aspirate evaluation. Management is with steroids, avoidance of the underlying inciting agent, and supportive interventions.
  • Acute eosinophilic leukemia: a neoplastic disease characterized by a marked increase in the number of immature eosinophils (unlike CEL) in the blood and/or marrow, > 10% blast forms in bone marrow, and infiltration of tissues (nervous system and bone) with immature eosinophil forms. Anemia, thrombocytopenia, hepatosplenomegaly, and susceptibility to infection are also seen. Diagnosis is made by history and physical examination findings along with blood and marrow evaluations. Management is with chemotherapy and hematopoietic stem cell transplantation.
  • Systemic mastocytosis with eosinophilia: a type of mast cell disease caused by the accumulation of functionally defective mast cells, associated with KIT mutations (often KIT D816V) in most patients. A characteristic skin rash (urticaria pigmentosa) and GI symptoms are noted along with hepatosplenomegaly. Diagnosis is made by the characteristic skin lesions and dense infiltrates of mast cells in marrow or in extracutaneous organs. Tests show elevated serum tryptase and positive mutation screening for KIT D816V. Management is with corticosteroids, symptomatic interventions, and different agents (midostaurin, hydroxyurea, and others in different settings).
  • PDGFRA-mutated eosinophilia: prominent eosinophilia with platelet-derived growth factor receptors α (PDGFRA on chromosome 4q12) and β (PDGFRB on chromosome 5q31-q32) are affected in activating mutations. Genetic studies in cases with hypereosinophilia help distinguish these conditions. Both PDGFRA– and PDGFRB-related disorders are responsive to imatinib.

Other chronic myeloproliferative neoplasms

  • Chronic myeloid leukemia: a malignant proliferation of WBCs, a myeloproliferative disorder with fairly normal differentiation. The underlying pathology involves translocation of genetic material resulting in a Philadelphia chromosome with deregulated tyrosine kinase production. Symptoms include constitutional complaints, early satiety, sternal tenderness, and hepatosplenomegaly. Laboratory studies show elevated WBCs and a peripheral smear with increased numbers of immature cells. Management focuses on tyrosine kinase inhibition.
  • Primary myelofibrosis: a chronic myeloproliferative neoplasm characterized by fibrosis of the bone marrow and extramedullary hematopoiesis in the spleen and liver. The condition is linked to mutations in JAK2, CALR, and MPL. Clinical findings are severe fatigue, splenomegaly, hepatomegaly, and anemia. The peripheral smear is leukoerythroblastic and contains precursors of WBCs and RBCs, nucleated RBCs, and teardrop cells. Diagnosis is made by bone marrow examination and molecular testing. Management includes allogeneic hematopoietic cell transplantation, and the medications ruxolitinib and fedratinib.
  • PCV: an unregulated overproduction of hematopoietic stem cells, mainly the RBCs, despite low levels of EPO. There is a gain-of-function mutation in the JAK2 gene. The majority of patients present with hyperviscosity symptoms. Management includes phlebotomy, low-dose aspirin, and myelosuppressive therapies.
  • Essential thrombocythemia: a proliferation of megakaryocytes usually due to JAK2, CALR, and MPL mutations resulting in thrombocytosis. Clinical manifestations are headaches, visual disturbances, and erythromelalgia. Excessive counts of platelets result in both thrombosis and bleeding. Management aims to reduce platelet count (with medications such as hydroxyurea) and decrease the risk of thrombosis (by systemic anticoagulation and/or antiplatelet agents).

References

  1. Cheah, C.Y., Burbury, K., Apperley, J.F., et al. (2014). Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood. 123(23),3574–3577. https://pubmed.ncbi.nlm.nih.gov/24687085/
  2. Crane, M.M., et al. (2010). Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol. 126(1),179–181. https://pubmed.ncbi.nlm.nih.gov/20639012/
  3. Gotlib, J. (2017). World Health Organization‐defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 92(11),1243– 1259. https://doi.org/10.1002/ajh.24880
  4. Helbig, G., et al. (2012). Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation. Am J Hematol. 87(6),643–645. https://pubmed.ncbi.nlm.nih.gov/22473587/
  5. National Cancer institute. (2020). Chronic Myeloproliferative Neoplasms Treatment (PDQ®)–Health Professional Version. Retrieved May 2, 2021, from https://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq#_101
  6. Nguyen, L., Zhang, L. (2021). Myeloproliferative neoplasms (MPN) Chronic eosinophilic leukemia. Pathologyoutlines. Retrieved May 2, 2021, from https://www.pathologyoutlines.com/topic/myeloproliferativeCEL.html
  7. Ogbogu, P.U., Bochner, B.S., Butterfield, J.H., et al. (2009). Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 124(6),1319–1325.e3. https://pubmed.ncbi.nlm.nih.gov/19910029/
  8. Roufosse, F., Klion, A., and Weller, P. (2021). Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis. In Larson, R. (Ed.), UpToDate. Retrieved April 17, 2021, from https://www.uptodate.com/contents/hypereosinophilic-syndromes-clinical-manifestations-pathophysiology-and-diagnosis
  9. Samavedi, A.V., (2020). Hypereosinophilic Syndrome. Medscape. Retrieved April 17, 2021, from https://reference.medscape.com/article/202030-overview
  10. Thakral, B., Wang, S. (2018). Myeloproliferative and “Overlap” Myelodysplastic/Myeloproliferative Neoplasm. In Hematopathology (Third Edition), Elsevier. https://www.sciencedirect.com/science/article/pii/B9780323479134000173
  11. Tefferi, A., Longo D.L. (2018). Less common hematologic malignancies. In Jameson, J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  12. Valent, P., Klion, A.D., Horny, H.P., et al. (2012). Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 130(3),607–612.e9. https://pubmed.ncbi.nlm.nih.gov/22460074/
  13. Weller, P., and Klion, A. (2021). Eosinophil biology and causes of eosinophilia. In Mahoney, D, and Newburger, P. (Ed.), UpToDate. Retrieved April 17, 2021, from https://www.uptodate.com/contents/eosinophil-biology-and-causes-of-eosinophilia

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