Myelodysplastic/myeloproliferative neoplasm with neutrophilia

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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[1][2]. 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[3][4].

The median patient age at diagnosis is in the seventh or eighth decade of life[4][5][6]. Rare cases of aCML has also been reported in teenagers. The reported male-to female ratio is approximately 1:1[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[5][7][6].

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[8].
    • 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).
Please incorporate this section into the relevant tables found in:
  • 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[4]; most of the remaining patients die of marrow failure[7][9].

Predictors of worse prognosis:

  • Age > 65 years
  • Female sex
  • White blood cell count > 50 x 109/L, thrombocytopenia and hemoglobin level < 10 g/dL[9].
  • Increased blasts in blood and/or bone marrow.

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)

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 [5][6].
  • Isolated isochromosome 17q rare (most present with features of CMML instead of aCML).

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

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[10] Other: conferring self-renewal capability to myeloid progenitors[11] GOF 25-38%[12][13]

Other Mutations

Gene/Mutation Prevalence[4]
RAS (KRAS/NRAS) 35%
ETNK1: H243Y and N244S 8.8%[14]
JAK2: V617F 7%
CSF3R <10%
CALR <10%
APC2 6%[13]

Mutations in TET2, ASXL1, EZH2 and SRSF2 (overlapping with CMML) are not uncommon in aCML[15].

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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  1. ↑ 1.0 1.1 Orazi A, et al., (2017). Atypical chronic myeloid leukaemia, BCR-ABL1-negative, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p87-89.
  2. ↑ Czader, M and Orazi, A. Chapter 45. Myelodysplastic/Myeloproliferative Neoplasms and Related Diseases. In Orazi A, Foucar K, Knowles DM. eds. Knowles Neoplastic Hematopathology. Riverwoods, IL: Wolters Kluwer Health; 2013:1148-1150.
  3. ↑ A, Orazi; et al. (2008). "The Myelodysplastic/Myeloproliferative Neoplasms: Myeloproliferative Diseases With Dysplastic Features". PMID 18480833.
  4. ↑ 4.0 4.1 4.2 4.3 Sa, Wang; et al. (2014). "Atypical Chronic Myeloid Leukemia Is Clinically Distinct From Unclassifiable Myelodysplastic/Myeloproliferative Neoplasms". doi:10.1182/blood-2014-02-553800. PMC 4067498. PMID 24627528.CS1 maint: PMC format (link)
  5. ↑ 5.0 5.1 5.2 Jm, Hernández; et al. (2000). "Clinical, Hematological and Cytogenetic Characteristics of Atypical Chronic Myeloid Leukemia". PMID 10847463.
  6. ↑ 6.0 6.1 6.2 P, Martiat; et al. (1991). "Philadelphia-negative (Ph-) Chronic Myeloid Leukemia (CML): Comparison With Ph+ CML and Chronic Myelomonocytic Leukemia. The Groupe Français De Cytogénétique Hématologique". PMID 2070054.
  7. ↑ 7.0 7.1 R, Kurzrock; et al. (2001). "BCR Rearrangement-Negative Chronic Myelogenous Leukemia Revisited". PMID 11387365.
  8. ↑ Brizard, A.; et al. (1989). "THREE CASES OF MYELODYSPLASTIC-MYELOPROLIFERATIVE DISORDER WITH ABNORMAL CHROMATIN CLUMPING IN GRANULOCYTES". British Journal of Haematology. 72 (2): 294–295. doi:10.1111/j.1365-2141.1989.tb07703.x. ISSN 0007-1048.
  9. ↑ 9.0 9.1 M, Breccia; et al. (2006). "Identification of Risk Factors in Atypical Chronic Myeloid Leukemia". PMID 17043019.
  10. ↑ R, Acuna-Hidalgo; et al. (2017). "Overlapping SETBP1 Gain-Of-Function Mutations in Schinzel-Giedion Syndrome and Hematologic Malignancies". doi:10.1371/journal.pgen.1006683. PMC 5386295. PMID 28346496.CS1 maint: PMC format (link)
  11. ↑ Oakley, Kevin; et al. (2012). "Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10". Blood. 119 (25): 6099–6108. doi:10.1182/blood-2011-10-388710. ISSN 0006-4971. PMC 3383018. PMID 22566606.CS1 maint: PMC format (link)
  12. ↑ Mughal, T. I.; et al. (2015). "An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms". Haematologica. 100 (9): 1117–1130. doi:10.3324/haematol.2014.114660. ISSN 0390-6078. PMC 4800699. PMID 26341525.CS1 maint: PMC format (link)
  13. ↑ 13.0 13.1 Palomo, Laura; et al. (2020). "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms". Blood. doi:10.1182/blood.2019004229. ISSN 0006-4971.
  14. ↑ Gambacorti-Passerini, Carlo B.; et al. (2015). "Recurrent ETNK1 mutations in atypical chronic myeloid leukemia". Blood. 125 (3): 499–503. doi:10.1182/blood-2014-06-579466. ISSN 0006-4971.
  15. ↑ Faisal, Muhammad; et al. (2019). "Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia". Cancer Medicine. 8 (2): 742–750. doi:10.1002/cam4.1946. PMC 6382710. PMID 30635983.CS1 maint: PMC format (link)

Notes

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