Chronic Eosinophilic Leukemia, Not Otherwise Specified

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Chelsea D. Kramish; Daynna J.Wolff

Pending Review*

Cancer Category/Type

Myeloproliferative Neoplasm

Definition / Description of Disease

Chronic Eosinophilic Leukemia (CEL) is an autonomous, clonal proliferation of eosinophil precursor cells leading to persistently increased eosinophils in peripheral blood, bone marrow and peripheral tissues. The eosinophil count must be greater than or equal to 1.5 x 10^9/L in the blood with less than 20% blasts in the peripheral blood and bone marrow. Diagnosis of CEL is based upon evidence for clonality of myeloid cells or an increase in myeloblasts in peripheral blood (at least 2%) or bone marrow (at least 5%), in order to distinguish from hypereosinophilic syndrome (HES). [1]

Synonyms / Terminology

Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL, NOS)

Epidemiology / Prevalence

The true incidence is unknown, due to the difficulty of differentiating CEL from idiopathic HES. However, CEL, NOS appears to be more common in men. The reported median age of occurrence is in the seventh decade of life. [1]

Clinical Features

CEL, NOS is sometimes discovered incidentally in otherwise asymptomatic individuals. In other instances, patients experience constitutional symptoms including weight loss, night sweats, fever, fatigue, cough, angioedema, muscle pain, pruritis and diarrhea. Endomyocardial fibrosis with ensuing restrictive cardiomegaly is known to precipitate the most severe clinical presentation. Scarring of the bicuspid and mitral valves can lead to valvular regurgitation and intracardiac thrombi formation which may embolize to the brain and other organs. Cardiac failure may also occur. Peripheral neuropathy, central nervous system dysfunction and pulmonary symptoms due to lung infiltration as well as rheumatological findings are also common. [1]

Sites of Involvement

Peripheral blood and bone marrow are always involved. Tissue damage secondary to infiltration by eosinophils and the release of cytokines and humoral factors from eosinophil granules may lead to involvement of the heart, lungs, central nervous system, skin, liver, spleen and gastrointestinal tract. [1]

Morphologic Features

Microscopic evaluation of CEL shows eosinophilia in the peripheral blood with small numbers of eosinophilic myelocytes and promyelocytes. Eosinophils are mainly mature and may have sparse granulation, cytoplasmic vacuolation, nuclear hypersegmentation or hyposegmentation, and increased size. Of note, these characteristics alone may not be able to differentiate CEL, NOS from reactive eosinophilia. Significant dysplasia of other myeloid cells contributes toward the diagnosis of CEL, NOS. Neutrophilia and mild basophilia have been reported as well. Blast cells may be present but compose less than 20% of the cells. Greater or equal to 2% myeloblasts in peripheral blood is suggestive of CEL, NOS. [1]

Bone marrow is hypercellular and in most cases eosinophil maturation is orderly. Erythropoiesis and megakaryoctopoiesis are typically normal. Marrow fibrosis is present in approximately one third of cases. 5-20% myeloblasts in bone marrow is suggestive of CEL, NOS. Charcot-laden crystals are often present. [1]

Immunophenotype

No specific immunophenotype has been identified.

Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

No single or specific genetic abnormality has been identified in CEL, NOS. Rearrangement of PDGFRA, PDGFRB, or FGFR1 excludes the diagnosis of CEL, NOS. PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 are also specifically excluded. [1] Three unique cases of myeloid/lymphoid neoplasm with eosinophilia have shown FLT3 rearrangement: one with t(13;14)(q12;q32)/TRIP11-FLT3 rearrangement, and two with ETV6-FLT3. Eosinophilia and FLT3 rearrangement typically shows myeloproliferative neoplasms, most frequently CEL, NOS, and T-ALL. [5] A unique case of CEL,NOS with a novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and confirmed by PCR in a 54 year old man presenting with cough and dyspnea. [6]

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 5%
EXAMPLE t(8;21)(q22;q22)	EXAMPLE 5'RUNX1 / 3'RUNXT1	EXAMPLE der(8)	EXAMPLE 5%

Characteristic Chromosomal Aberrations / Patterns

A recurrent karyotypic abnormality typically observed in myeloid disorders such as gain of chromosome 8, loss of chromosome 7 or isochromosome 17q supports a diagnosis as well as the presence of a translocation. [1] [1] Morsia et al demonstrated cytogenetic abnormalities in 15 of 17 (88.2%) patients diagnosed with CEL, NOS including trisomy 8 (n = 4), and complex karyotype (n = 3). [4]

Genomic Gain/Loss/LOH

Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:0-1000000
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

JAK2 mutations have been identified, however mutations in ASXL1, TET2 and EZH2 appear to be common. [1] The study by Morsia et al. of 17 CEL patients demonstrated two patients each with 13q, 20q deletion, and chromosome 1 abnormalities, one patient with monosomy 7 and one with 3q deletion. All seven patients with NGS studies harbored one or more mutations; ASXL1 (42.9%); IDH1 (28.6%), and one each (14.3%) with TP53, SRSF2, SH2B3, STAT5B, KDM6A and NF1 mutations. [4] A novel JAK2 exon 13 insertion/deletion mutant has been identified and described by Patel et al. in a patient fulfilling diagnostic criteria for both PV and CEL. This study demonstrated that JAK2ex13InDel bears mechanistic resemblance to JAK2V617F but can activate STAT5 in the absence of βc family cytokines IL-3, IL-5, and GM-CSF, potentially promoting eosinophilic differentiation. [7] Keleman et al. discussed STAT5B mutations as reported in four cases: two cases of CEL, NOS; one case of CMML with eosinophilia; and one case of MDS with eosinophilia, respectively. While the presence of a STAT5B N642H mutation may be a potential marker of chronic eosinophilic neoplasms, similar mutations have been described in nonclonal HE and may not be independently sufficient to establish a diagnosis of CEL, NOS. [8]

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Diagnostic Testing Methods

A detailed history, physical exam, blood count and examination of blood smear are key diagnostic measures. The process of making a diagnosis heavily relies on the exclusion of reactive eosinophilia, and myeloid neoplasms with the previously mentioned rearrangements or fusions. [1] Wang et al. demonstrated that targeted next generation sequencing helps to establish clonality in a portion of patients with hypereosinophilia that would otherwise be diagnosed with idiopathic hypereosinophilic syndrome. [3]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Although survival is variable, acute transformation is common and prognosis is typically poor. The median survival time in one small series was 22.2 months. Response to imatinib has been reported but is uncommon. Treatment with Interferon alpha leading to cytogenic remission has been reported in 3 cases with translocations with a 5q31-33 breakpoint. Complete hematologic response has been achieved in one reported case of CEL with ETV6/FLT3 fusion, with the off-label use of FLT3-inhibitor, sorafenib.[2] Unfavorable prognostic findings include marked splenomegaly, blasts in the blood or increased blasts in bone marrow, cytogenetic abnormalities, and dysplastic features in other myeloid lineages. [1] According to a study of 17 cases defined by WHO-2016 standards, univariate survival analysis showed predictors of inferior survival included megakaryocytic atypia (P = .01), peripheral blood eosinophilic atypia (P = .024), LDH (P = .046) and abnormal karyotype (P = .020). [4] Of these patients, the most frequently utilized first line agents were hydroxyurea as a single agent or in combination with steroids, steroids as a single agent, or in combination. Half of patients treated with hydroxyurea based regimens responded with a persistent decline in eosinophil count over 17.5 months. Approximately one third of patients demonstrated response to steroids for a median duration of 13 months. Three of these patients were treated with imatinib of which two had normalization of eosinophil count. [4] Imatinib was successful in treatment of the individual case of CEL,NOS with novel fusion gene involving PDGFRB and GCC2 with disappearance of the fusion gene in bone marrow after three months. [6]

Links

https://ccga.io/index.php/Chronic_Eosinophilic_Leukemia,_Not_Otherwise_Specified?veaction=edit&section=2

References

1. Bain B.J, et al., (2017). Chronic eosinophilic leukemia, NOS, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p54-56
2. Ricci, F., Balducci, S., Guerrini, F., Grassi, S., Ciabatti, E., Baratè, C., . . . Galimberti, S. (2020). Sorafenib Induced Complete Cytogenetic and Molecular Response in a Chronic Eosinophilic Leukemia Case with t(12;13) Translocation. Clinical Hematology International, 2. doi:10.2991/chi.k.200714.001
3. Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian RP, Geyer JT, George TI, Czuchlewski DR, Foucar K, Rogers HJ, Hsi ED, Bryan Rea B, Bagg A, Dal Cin P, Zhao C, Kelley TW, Verstovsek S, Bueso-Ramos C, Orazi A. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016 Aug;29(8):854-64. doi: 10.1038/modpathol.2016.75. Epub 2016 May 13. PMID: 27174585.
4. Morsia, E., Reichard, K., Pardanani, A., Tefferi, A., & Gangat, N. (2020). WHO defined chronic eosinophilic leukemia, not otherwise specified ( CEL , NOS ): A contemporary series from the Mayo Clinic. American Journal of Hematology, 95(7). doi:10.1002/ajh.25811
5. Shao, H., Wang, W., Song, J., Tang, G., Zhang, X., Tang, Z., . . . Zhang, L. (2020). Myeloid/lymphoid neoplasms with eosinophilia and FLT3 rearrangement. Leukemia Research, 99, 106460. doi:10.1016/j.leukres.2020.106460
6. Iriyama N, Takahashi H, Naruse H, Miura K, Uchino Y, Nakagawa M, Iizuka K, Hamada T, Hatta Y, Nakayama T, Takei M. A novel fusion gene involving PDGFRB and GCC2 in a chronic eosinophilic leukemia patient harboring t(2;5)(q37;q31). Mol Genet Genomic Med. 2019 Apr;7(4):e00591. doi: 10.1002/mgg3.591. Epub 2019 Jan 29. PMID: 30697976; PMCID: PMC6465652.
7. Patel AB, Franzini A, Leroy E, Kim SJ, Pomicter AD, Genet L, Xiao M, Yan D, Ahmann JM, Agarwal AM, Clair P, Addada J, Lambert J, Salmon M, Gleich GJ, Cross NCP, Constantinescu SN, O'Hare T, Prchal JT, Deininger MW. JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera. Blood. 2019 Dec 26;134(26):2388-2398. doi: 10.1182/blood.2019001385. PMID: 31697804; PMCID: PMC6933291.
8. Katalin Kelemen, MD, PhD, Leonie Saft, MD, Fiona E Craig, MD, Attilio Orazi, MD, Megan Nakashima, MD, Gerald B Wertheim, MD, PhD, Tracy I George, MD, Hans-Peter Horny, MD, Rebecca L King, MD, Leticia Quintanilla-Martinez, MD, Sa A Wang, MD, Lisa M Rimsza, MD, Kaaren K Reichard, MD, Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders: Report of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop, American Journal of Clinical Pathology, , aqaa244, https://doi.org/10.1093/ajcp/aqaa244

Notes

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