Definition and characteristics of CEL,NOS

The unspecified chronic eosinophilic leukemia (CEL, NOS) is characterized by clonal eosinophilia and is classified as myeloproliferative neoplasia (MPN). It is a very rare and aggressive disease in which clonal proliferation of eosinophilic progenitor cells causes an increase of eosinophils in peripheral blood, bone marrow and peripheral tissue. A leukemic infiltration or the release of cytokines, enzymes or other proteins of eosinophils can lead to organ damage of e.g. heart, lung, skin, gastrointestinal tract or the central nervous system.

Classification of CEL, NOS

Diagnostic criteria according to WHO 2017:

1. Eosinophilia (eosinophil number ≥1.5 x 109/L)

 

2. WHO criteria for a BCR-ABL1 positive CML, a BCR-ABL1 negative atypical CML, PV, ET, PMF, CNL or CMML are not met

 

3. No rearrangement of PDGFRA, PDGFRB or FGFR1, and no PCM1-JAK2, ETV6-JAK2 or BCR-JAK2 fusion

 

4. Blast cells constitute <20% of the cells in the peripheral blood and bone marrow, and inv(16)(p13q22), t(16;16)(p13;q22), t(8;21)(q22;q22), and other diagnostic features of acute myeloid leukemia are absent

 

5. There is a clonal cytogenetic or molecular genetic abnormality
or
Blast cells account for ≥2% of cells in peripheral blood or ≥5% in bone marrow

 

The diagnosis of CEL, NOS is usually made by excluding other hematological neoplasm that may have eosinophilia. Excluded are neoplasms that have a Philadelphia chromosome or a BCR-ABL1 fusion, a PDGFRA, PDGFRB or FGFR1 rearrangement, or a PCM1-JAK2, ETV6-JAK2 or BCR-JAK2 fusion. According to the WHO, the CEL, NOS shows an eosinophil count ≥1.5 x 109/L in peripheral blood and a blast percentage of <20% in peripheral blood and bone marrow. In addition, diagnosis requires either the clonality of a cyto or molecular genetic alteration or an increase in blasts from ≥2% in peripheral blood or from ≥5% in bone marrow. Here it is to be noted that mutations in e.g. TET2, ASXL1 and DNMT3A can occur in older people without association to a hematological neoplasm (see CHIP in Hematology) and should therefore be considered critically for a clonality detection.

If clonality can neither be proven by the detection of a cyto or molecular genetic alteration nor an increase in the number of blasts, the diagnosis of an idiopathic hypereosinophilic syndrome (HES) should be made. Idiopathic hypereosionophilic syndrome is characterized by an eosinophilic number of ≥1.5 x 109/L for ≥6 months for which no underlying cause can be demonstrated. There is also evidence of involvement of organs and their dysfunction. Without these signs, the term idiopathic hypereosinophilia should be used. Eosinophilia can also be caused by the increased release of T-cell associated cytokines. Therefore, the presence of aberrant T lymphocytes should be excluded.

Diagnostics of CEL, NOS

Cytomorphology

By detecting eosinophilia, cytomorphology plays a central role in the diagnosis of CEL, NOS. It can also help to exclude differential diagnoses that may also cause eosinophilia.

Immunophenotyping

No specific immunophenotype has been described for CEL, NOS. Nevertheless, immunophenotyping is important for the exclusion of a T-lymphocyte-driven eosinophilia.

Chromosome analysis

No specific chromosome abnormality has been reported in CEL, NOS. However, chromosomal analysis may be important for clonality detection by detecting cytogenetic alterations, thus allowing to distinguish it from an idiopathic hypereosinophilic syndrome (HES). Various numerical and structural chromosomal alterations are found, which are also described for other myeloid neoplasms. These include, for example, trisomy 8, monosomy 7, an isochromosome 17q, 13q and 20q deletions and alterations of chromosome 1. Complex karyotypes may also occur (Morisa et al. 2020, Swerdlow et al. 2017).

FISH

In the diagnosis of CEL, NOS the FISH analysis is used especially to exclude the presence of specific rearrangements of PDGFRA, PDGFRB, JAK2 and FGFR1. Due to the high number of partner genes, FISH analysis is better suited than molecular genetics to exclude these rearrangements. In addition, it can be used as a complementary method to classical chromosome analysis in order to answer specific questions.

Molecular genetics

In the diagnosis of CEL, NOS, molecular genetics is used for the clonality detection of molecular genetic alterations and thus enables the differentiation from an idiopathic hypereosinophilic syndrome (HES). By means of next-generation sequencing, a fast and parallel analysis of several genes is possible. The mutations described in CEL, NOS include mutations in the genes ASXL1, IDH1, IDH2, TP53, SRSF2, SH2B3, STAT5B, KDM6A, TET2, JAK2, SETBP1, SF3B1, EZH2, CBL and NF1 (Morisa et al. 2020, Reiter & Gotlib 2017). However, in older people mutations may occur without association to hematological neoplasm. If in the absence of signs of hematological neoplasm and absence of cytopenia mutations with a mutation load of ≥2% can be detected in genes that are typically mutated in myeloid neoplasms, clonal hematopoiesis of indeterminate potential (CHIP in hematology) is present. The most frequently affected genes are TET2, ASXL1 and DNMT3A (Steensma 2018). Therefore, these genes should be critically reviewed for clonality detection in the diagnosis of CEL, NOS.

Prognosis and Therapy of CEL, NOS

For CEL, NOS an unfavourable prognosis is described. In a cohort of 10 patients the median overall survival was 22.2 months. Of the 10 patients, 5 showed transformation into acute leukemia after a median of 20 months (Helbig et al. 2012). According to the WHO, splenomegaly, peripheral blood blasts or increased bone marrow blasts, cytogenetic aberrations and dysplastic features in other myeloid cell lines are associated with an unfavourable prognosis.

There is no standardized treatment protocol for patients with CEL, NOS. In some patients hydroxyurea may be used to control leucocytosis, eosinophilia and splenomegaly. In addition, treatment with steroids, either in combination with Hydroxyurea or as single therapy, is also described. In addition, positive results have been obtained using interferon-α in patients who did not respond to other therapies, such as prednisone and/or hydroxyurea. For younger and physically fit patients, stem cell transplantation should be considered (Helbig et al. 2012, Morisa et al. 2020, Swerdlow et al. 2017).

Since CEL, NOS is a very rare entity and diagnosis is sometimes difficult to establish, previous studies have only included a small number of patients. Therefore, it is not possible at this time to make a clear statement about exact prognostic factors and treatment strategies.

References

Helbig G et al. Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation. American Journal of Hematology 2012;87(6):643-645.

Morisa E et al. WHO defined chronic eosinophilic leukemia, not otherwise specified (CEL, NOS ): A contemporary series from the Mayo Clinic. American Journal of Hematology 2020;95(7):E172-E175.

Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood 2017;129(6): :704-714.

Steensma DP Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv. 2018;27;2(22):3404-3410

Swerdlow SH et al. WHO classification of tumours of haematopoetic and lymphoid tissue. International Agency of Research on Cancer 2017; 4. überarbeitete Version.