Atypical Chronic Myeloid Leukemia (aCML)

and Chronic Neutrophilic Leukemia (CNL)

Related Cases: hp-299


Proposed WHO Diagnostic Criteria for Chronic Neutrophilic Leukemia

  • Major criteria

    1. Peripheral blood leukocytosis, >13×109/L

    2. 80% Neutrophils or bands

    3. Presence of CSF3R T618I or other membrane proximal CSF3R mutations

  • Minor criteria

    1. Bone marrow:

      • Hypercellular

      • Increased granulocytic proliferation without significant left shift

      • No dysgranulopoiesis

    2. Peripheral blood:

      • <10% immature granulocytes

      • <2% myeloblasts

      • <1×109 absolute monocyte count or

      • < 10% monocyte percentage

      • No dysgranulopoiesis

    3. Presence of a clonal marker or absence of  evidence for reactive/secondary  granulocytosis, including plasma cell neoplasm

    4. Absence of BCR-ABL1

    5. Not meeting WHO diagnostic criteria for any other myeloid neoplasm

  • Diagnosis requires presence of all three major criteria or the first two major criteria and all minor criteria.


WHO Diagnostic Criteria Atypical Chronic Myeloid Leukemia (aCML)

  • Peripheral blood:

    • Neutrophilic leukocytosis, WBC >13 × 109/L

    • Left shift, immature granulocytes >10%

    • Prominent dysplasia

    • No monocytosis and basophilia

    • < 20% blasts in the blood

  • Bone marrow:

    • Hypercellular with marked hypergranulopoiesis and dysplasia

    • With or without dysplasia in erythroid or megakaryocytic lineages

    • <20% Myeloblasts

  • No rearrangements of BCR/ABL1, PDGFRA and PDGFRB


Overview of Chronic Neutrophilic Leukemia (CNL)

  • Clinical and laboratory features:
    • Persistent neutrophilic leukocytosis with minimal left shift
    • Hepatosplenomegaly
    • Elevated leukocyte alkaline phosphatase and vitamin B12 levels
  • Disease course:
    • Variable, median survival 23.5 months
    • Acceleration typically characterized by refractory neutrophilia, worsening organomegaly, and blastic transformation
    • Median time to AML transformation, 21 months
    • Most frequent causes of death: Intracranial hemorrhage, progressive disease/blastic transformation, and chemotherapy or transplantation induced toxicity

Overview of Atypical Chronic Myeloid Leukemia (aCML)

  • Clinical and laboratory features:
    • Neutrophilic leukocytosis, WBC >13 × 109/L
    • Left shift, immature granulocytes >10%
    • Prominent dysplasia
    • No monocytosis and basophilia
    • < 20% blasts in the blood and marrow
    • Splenomegaly
    • Hypercellular bone marrow with myeloid hyperplasia and prominent granulocytic dysplasia or multilineage dysplasia
  • Disease course:
    • Overall median survival 25 months
    • Transformation to AML, 40%, 18 months

Cytogenetic and Molecular Features of CNL and aCML

  • Mostly normal cytogenetics
  • Most common chromosomal abnormalities: Nonspecific, trisomy 8 and del (20q)
  • Lack of BCR/ABL rearrangement
  • Lack of JAK2 mutation in most cases
  • Recently identified mutations of CSF3R and SETBP1 in most cases

 Mutation of CSF3R (Receptor for colony-stimulating factor 3):

  • CNL (8/9, 89%), aCML (8/20, 40%)
  • Nonsense or frame-shift mutations, most commonly T618I
  • Functions of CSF3R: Signal downstream through both JAK and SRC pathways; Promotes growth, survival and differentiation of myeloid cells, through binding to G-CSF
  • Truncation mutations
    • Cytoplasmic tail
    • Result in increased expression of CSF3R
    • Activate downstream SFKs and TNK2
    • Leukemic cells highly sensitive to dasatinib
    • May also be sensitive to JAK kinase inhibitors
  • Membrane proximal mutations
    • Point mutations
    • Completely ligand-independent function
    • Signal through JAK–STAT pathway
    • Candidates for JAK kinase inhibitors, ruxolitinib

Mutation of SETBP1 ( SET binding protein)

  • SETBP1 mutation: MDS/MPN 10%, CMML 4%; not in AML, ALL, CLL or solid tumor
  • SETBP1 mutations in aCML were associated with higher white blood cell counts at diagnosis and poorer survival
  • Normal function of SETBP1: Interacts with SET, a negative regulator of PP2A, and protects SET from protease cleavage, thus retaining SET activity to repress PP2A
  • CSF3R and SETBP1 mutations, not mutually exclusive in CNL/aCML
  • In a study with 29 patients, 21% with both CSF3R and SETBP1 mutations, 31% of samples with CSF3R mutations only, and 7% with SETBP1 mutations only

Diagnostic Workup for Persistent Neutrophilia


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  • Leukemia (2013) 27, 1870–1873
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Last updated: 05/18/2015