Status: April 2020

aCML - Definition

BCR-ABL1-negative atypical chronic myeloid leukemia (aCML) is a rare entity from the overlapping area of myelodysplastic and myeloproliferative diseases.

aCML - Classification

According to the WHO classification 2017, aCML is a leukemic disorder with myelodysplastic as well myeloproliferative features (MDS/MPN).

aCML WHO Classification 2017 (Swerdlow et al. 2017)

Myelodysplastic/myeloproliferative neoplasia

Atypical chronic myeloid leukaemia (aCML), BCR-ABL1-negative

Diagnostic criteria according to WHO 2017:

  • 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

 

Diagnostics of aCML

Cytomorphology

Cytomorphology serves to differentiate the disease from other myeloproliferative diseases (MPN), CMML and myelodysplastic syndrome (MDS) and to secure the diagnosis. It is also required for classification according to WHO.

Chromosome analysis

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.

Molecular genetics

Recurrent mutations in 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.

Prognosis of aCML

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).

aCML - Recommendation

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.

References

Breccia M et al. Identification of risk factors in atypical chronic myeloid leukemia. Haematologica 2006;91(11):1566–1568.

Gambacorti-Passerini CB et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood 2015;125(3):499-503.

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.

Meggendorfer M et al. Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica 2014;99(12):e244-e246.

Meggendorfer M et al. The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms. Haematologica 2018;103(5):e192-e195.

Onida et al. Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 2002;95(8):1673–1684.

Piazza R et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 2013;45(1):18-24.

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

Wang SA et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 2014;123(17):2645-2651.