Chronic neutrophilic leukemia (CNL)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with chronic neutrophilic leukemia (CNL). We have summarized the most important information on classification and diagnostic methods at MLL. In addition, we provide further links about CNL, so that you can inform yourself in more detail.

Chronic neutrophilic leukemia (CNL): Classification

Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm that characteristically presents as a triad of persistent neutrophilia, bone marrow hypercellularity, and hepatosplenomegaly. By WHO definition, isolated neutrophilia is a key feature of CNL that helps differentiate CNL from other chronic myeloid neoplasms (WHO 2022). Thus, compared to CML, CNL is characterized by more mature granulopoietic forms (Szuber et al. 2022).

In 2013, a mutation in the colony stimulating factor 3 receptor (CSF3R) was identified in the majority of CNL patients studied (Maxson et al. 2013), which is now designated as a defining genomic abnormality by the WHO (WHO 2022).

The diagnosis requires exclusion of reactive neutrophilia and other myeloproliferative and myelodysplastic/​myeloproliferative neoplasms. According to WHO 2022, the following criteria serve to establish the diagnosis (WHO 2022):

Table 1: WHO diagnostic criteria in CNL (WHO 2022)


1.
  • Peripheral blood white blood cell count ≥ 25 × 109/ L
  • Segmented neutrophils plus banded neutrophils constitute ≥ 80% of the white blood cells
  • Neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) constitute < 10% of the white blood cells
  • Myeloblasts rarely observed
  • Monocytes constitute <10% of peripheral blood leukocytes; absolute monocytosis not  meeting criteria for CMML
  • No dysgranulopoiesis

2.
  • Hypercellular bone marrow
  • Neutrophil granulocytes increased in percentage and number
  • Neutrophil maturation appears normal
  • Myeloblasts constitute < 5% of the nucleated cells

3.

Not meeting WHO criteria for BCR::ABL1-positive CML, PV, ET oder PMF

4.

No evidence of disease-defining gene rearrangements such as PDGFRA, PDGFRB or FGFR1 and no PCM1::JAK2 fusion

5.

Presence of CSF3R p.T618I or another activating CSF3R mutation, OR persistent neutrophilia (≥ 3 months), splenomegaly, and no identifiable cause of reactive neutrophilia including absence of a plasma cell neoplasm or, if a plasma cell neoplasm is present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies

Chronic neutrophilic leukemia (CNL): Diagnostic methods and their significance

Chronic neutrophilic leukemia (CNL): Prognosis

The prognosis of CNL is variable: disease progression ranges from latent to aggressive (survival from 6 months to > 20 years). Neutrophilia is usually progressive and anemia and thrombocytopenia may follow - if pancytopenia occurs, survival is likely to worsen accordingly. The development of myelodysplastic features may be a sign of transformation to AML (WHO 2022).

Cases with an ASXL1 mutation present have been described as prognostically unfavorable (Elliott et al. 2015, WHO 2022). In contrast, patients with a CSF3R germline mutation appear to have better survival than patients with somatic mutations (Kojima et al. 1999, Druhan et al. 2016, Duployez et al. 2019).

The following overview can be used to calculate a risk score (Onkopedia-Leitlinie CNL 2023):

Feature

Score

Thrombocytopenia <160*109/L

2

Leukocytosis >60*109/L

1

ASXL1 mutation

1

Legend: 2-4 points = high risk, 0-1 points = low risk.

Chronic neutrophilic leukemia (CNL): Therapy

Due to its rarity, there is currently no standard therapy for the treatment of CNL. Allogeneic stem cell transplantation is the only curative therapeutic option to date. The development of disease-modifying therapies therefore represents a major unmet need (Szuber et al. 2022). A treatment algorithm is presented in the new Onkopedia guideline on CNL.

Status: July 2023

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