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 Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
• Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera (PCV)
• Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis (PMF)
• Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. 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 Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes
• Myeloid stem cell: eventually differentiates into platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. 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 Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets)
  • Erythropoietin (EPO) → differentiation to erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes (RBCs)

Eosinophilia

• Overproduction of eosinophils in bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, weight loss, night sweats)
• Symptoms related to:
  • Anemia: fatigue, palpitations
  • Thrombocytopenia: bruising, petechiae 
• Hepatosplenomegaly
• Can have overlapping symptoms (associated with eosinophilic activation): 
  • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
  • Dermatologic: cutaneous lesions, rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes
  • Pulmonary/respiratory: cough, asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • GI: gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis/ diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Rheumatologic: vasculitis, arthralgia
  • Cardiac: 
    • Cardiomegaly, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies (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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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 CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • PCV
    • ET
    • PMF
    • CNL
  • inv(16)(p13q22) or t(16;16)(p13;q22)
  • Myelodysplastic syndrome/myeloproliferative neoplasm (chronic myelomonocytic leukemia or atypical CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia)
  • Lymphocytic variant of hypereosinophilia 
• No rearrangement of PDGFRA, PDGFRB, FGFR1, or with PCM1-JAK2

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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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

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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables.
  • 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 Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests are CBC with differential, blood chemistries, and potential bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, and infiltration of tissues ( nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System and bone) with immature eosinophil forms. Anemia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin rash ( urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) pigmentosa) and GI symptoms are noted along with hepatosplenomegaly. Diagnosis is made by the characteristic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions and dense infiltrates of mast cells in marrow or in extracutaneous organs. Tests show elevated serum tryptase and positive mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Chronic myeloid leukemia Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. 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 Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis: a chronic myeloproliferative neoplasm characterized by fibrosis of the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow and extramedullary hematopoiesis in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. The condition is linked to mutations in JAK2, CALR, and MPL. Clinical findings are severe fatigue, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, hepatomegaly, and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview. The peripheral smear is leukoerythroblastic and contains precursors of WBCs and RBCs, nucleated RBCs, and teardrop cells. Diagnosis is made by bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the JAK2 gene. The majority of patients present with hyperviscosity symptoms. Management includes phlebotomy, low-dose aspirin, and myelosuppressive therapies.
• Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. 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 Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. 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 Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents).