HAEM5:Myelodysplastic/myeloproliferative neoplasm with neutrophilia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Atypical Chronic Myeloid Leukemia (aCML), BCR-ABL1 Negative.

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Primary Author(s)*

Linsheng Zhang, MD, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myelodysplastic/myeloproliferative neoplasms
Type	N/A
Subtype(s)	Myelodysplastic/myeloproliferative neoplasm with neutrophilia

Definition / Description of Disease

Atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML) presents with myelodysplastic as well as myeloproliferative features at the time of disease onset. The characteristic finding is blood leukocytosis with increase of dysplastic neutrophils and immature granulocytes. Bone marrow shows multilineage dysplasia.

• Before the diagnosis of aCML can be rendered, myeloid neoplasms with well defined genetic abnormalities such as BCR-ABL1 fusion; rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 must be ruled out.
• Myeloid neoplasm with features of aCML developed after chemo or radiation therapy is classified as therapy-related myeloid neoplasm.

Synonyms / Terminology

Atypical chronic myeloid leukemia, Philadelphia chromosome-negative (Ph-)

Atypical chronic myeloid leukemia, BCR-ABL1-negative

Epidemiology / Prevalence

The incidence of aCML is low; it is estimated that there are 1-2 aCML cases for every 100 cases of BCR-ABL1-positive chronic myeloid leukemia.

The median patient age at diagnosis is in the seventh or eighth decade of life. Rare cases of aCML has also been reported in teenagers. The reported male-to female ratio is approximately 1:1.

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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The primary symptoms are related to splenomegaly and blood cell changes like anemia and/or thrombocytopenia.

Sites of Involvement

• Blood and bone marrow are always involved.
• Involvement of spleen and liver is common.

Morphologic Features

BLOOD:

• The white blood cell count (WBC) ≥13 x 10⁹/L, cases >300 x 10⁹/L have been reported.
• Immature granulocytes, including promyelocytes, myelocytes, and metamyelocytes ≥10% of the leukocytes.
• Monocytes <10%.
• Mild basophilia.
• Dysplastic features observed in granulocytes:
  • Acquired Pelger-Huët anomaly
  • Other nuclear abnormalities (hypersegmentation with abnormally clumped nuclear chromatin or bizarrely segmented nuclei)
  • Multiple nuclear projections
  • Abnormal cytoplasmic granularity (usually hypogranularity).

• The syndrome of abnormal chromatin clumping is considered to be a morphologic variant of aCML.
  • Neutrophil nuclei show large well-separated blocks of heterochromatin and euchromatin
• Anemia and thrombocytopenia are common.

Blood smear. 600X (Wright stain)

BONE MARROW:

• Hypercellular with markedly increased myeloid-to-erythroid ratio (usually >10:1)
• Features of trilineage dysplasia
  • Dyserythropoiesis is present in about 40% of cases.
  • Dysgranulopoiesis with the changes in the neutrophil lineage similar to those in the blood.
  • Megakaryocytes quantitatively variable, usually normal or increased, frequently with dysmegakaryopoiesis, including micromegakaryocytes and small megakaryocytes with hypolobated nuclei.
• Mild fibrosis seen in some cases; may be more conspicuous with disease progression.

By definition, blasts <20% of blood leukocytes (usually <5%) and <20% of bone marrow nucleated cells.

Bone marrow aspirate smear, 200X (Wright stain).

Bone marrow biopsy, 100X (H&E stain).

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

editv4:Immunophenotype

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No specific immunophenotypic characteristics (flow cytometric analysis of blood and bone marrow usually report as normal, except mildly increased myeloblasts in some cases).

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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None.

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Genetic abnormalities and mutations in related genes provide evidence of a clonal process to support a neoplastic process. However, they are not specific for aCML.

The prognostic value of molecular/genetic abnormalities are not well studied yet.

Approximately 20-40% of aCML evolves to acute myeloid leukemia; most of the remaining patients die of marrow failure.

Predictors of worse prognosis:

• Age > 65 years
• Female sex
• White blood cell count > 50 x 10⁹/L, thrombocytopenia and hemoglobin level < 10 g/dL.
• Increased blasts in blood and/or bone marrow.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Karyotypic abnormalities are reported in as many as 80% of cases.

• Trisomy 8 and del(20q) most common.
• Abnormalities of chromosomes 13, 14, 17, 19 and 12 are also common .
• Isolated isochromosome 17q rare (most present with features of CMML instead of aCML).

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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None.

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence
SETBP1	D868N, S869N, G870S, I871T and D880N	Other: conferring self-renewal capability to myeloid progenitors	GOF	25-38%

Other Mutations

Gene/Mutation	Prevalence
RAS (KRAS/NRAS)	35%
ETNK1: H243Y and N244S	8.8%
JAK2: V617F	7%
CSF3R	<10%
CALR	<10%
APC2	6%

Mutations in TET2, ASXL1, EZH2 and SRSF2 (overlapping with CMML) are not uncommon in aCML.

Epigenomic Alterations

Not well studied yet.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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Frequently involved:

• Cell proliferation and survival (SETBP1)

Less commonly involved:

• JAK/STAT pathway (JAK2)
• PI3K/AKT and MAPK/ERK (CSF3R)

Genetic Diagnostic Testing Methods

Blood cell counts and blood smear review (differential cell counts and dysplastic features).

Bone marrow aspirate smear review and biopsy histopathology (abnormal maturation pattern, blast percentage, etc.).

Molecular/genetic studies are of critical importance to establish clonal evidence and rule out other entities with well defined genetic abnormalities.

• Chromosome analysis
• Fluorescence in situ hybridization (FISH) to rule out PDGFRA, PDGFRB or FGFR1 rearrangement, BCR-ABL1 and PCM1-JAK2 fusion.
• Next generation sequencing-based mutation profiling to detect mutations supporting a clonal process.

Familial Forms

None

Additional Information

None

Links

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References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Myelodysplastic/myeloproliferative neoplasm with neutrophilia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Myelodysplastic/myeloproliferative_neoplasm_with_neutrophilia.