- Peripheral blood leukocytosis ≥ 13x109/L, due to increased numbers of neutrophils and their precursors (i.e. promyelocytes, myelocytes and metamyelocytes), with neutrophil precursors constituting > 10% of the leukocytes
- Dysgranulopoiesis, which may include abnormal chromatin clumping
- No or minimal basophilia; basophils constitute < 2% of the peripheral blood leukocytes
- No or minimal monocytosis; monocytes constitute < 10% of the peripheral blood leukocytes
- Hypercellular bone marrow with granulocyte proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages
- <20% blasts in the blood and bone marrow
- No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement, or of PCM1-JAK2
- WHO criteria for BCR-ABL1-positive CML, PMF, PV or ET are not met
Chromosomal changes have been detected in about 40% of patients with aCML (Meggendorfer et al. 2018). The changes known from MPN and MDS occur. Most frequently an increase of chromosome 8 was observed, less frequently among others a monosomy 7 or 7q deletion, an isochromosome 17q or a complex karyotype (Wang et al. 2014). However, these changes are not specific for aCML.
Mutations in the SETBP1 gene ("set binding protein 1") have been described in about 25-30% of all cases (Piazza et al. 2013, Meggendorfer et al. 2013). Mutations in the ETNK1 gene ("ethanolamine kinase 1") were detected in 3-9% of aCML patients (Gambacorti-Passerini et al. 2014, Meggendorfer et al. 2018).
Furthermore, mutations in the genes ASXL1 (60%), TET2 (approx. 45%) and SRSF2 (approx. 35%) are found (Meggendorfer et al. 2018). However, these mutations are also found in other myeloid diseases. They can be used as clonal markers to differentiate aCML from reactive processes and for course diagnosis.
In contrast to chronic neutrophil leukemia (CNL), in which mutations in the CSF3R gene ("receptor for colony stimulating factor 3") have been frequently observed, they occur in only about 3% of patients with aCML (Meggendorfer et al. 2014).
In addition, low frequency mutations in CBL, RUNX1, NRAS and KRAS, among others, have been described in patients with aCML (Meggendorfer et al. 2018). At 9%, there are hardly any mutations in the JAK-STAT signalling pathway (JAK2, CALR, MPL), while the RAS signalling pathway (NRAS, KRAS, CBL) is more frequently affected at 37% (Meggendorfer et al. 2018).
It should be noted that according to WHO 2017, within the framework of differential diagnoses, a CNL should be morphologically excluded in the case of detection of a CSF3R mutation. Likewise, MPN should be excluded if a JAK2, CALR or MPL mutation is detected. In contrast, according to WHO 2017, the presence of a SETBP1 or ETNK1 mutation supports the diagnosis of atypical CML.
A leukocyte count of >50x109/L has been described in several studies as a prognostically negative parameter for aCML (Onida et al. 2002, Breccia et al. 2006, Wang et al. 2014). In some of these studies, an age >65 years, female sex and a hemoglobin level of <10 g/dL were also prognostically unfavourable. Furthermore, a negative influence of a SETBP1 mutation was shown (Piazza et al. 2013). 30-40% of patients with aCML show a transformation into AML (Wang et al. 2014).
It should be noted that according to WHO 2017, within the framework of differential diagnoses, a CNL should be morphologically excluded if a CSF3R mutation is detected. Similarly, in the case of detection of a JAK2, CALR or MPL mutation, an accelerated phase of an MPN should be excluded based on the history.
In contrast, according to WHO 2017, the presence of a SETBP1 or ETNK1 mutation supports the diagnosis of atypical CML.
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Meggendorfer M et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia 2013;27(9):1852-1860.
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