Chronic myelomonocytic leukaemia
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Chronic Myelomonocytic Leukemia (CMML).
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
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) | Chronic myelomonocytic leukaemia |
WHO Essential and Desirable Genetic Diagnostic Criteria
(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)
| WHO Essential Criteria (Genetics)* | |
| WHO Desirable Criteria (Genetics)* | |
| Other Classification |
*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
Related Terminology
(Instructions: The table will have the related terminology from the WHO autocompleted.)
| Acceptable | |
| Not Recommended |
Gene Rearrangements
Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: ABL1 | EXAMPLE: BCR::ABL1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | 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). BCR::ABL1 is generally favorable in CML (add reference). |
| EXAMPLE: CIC | EXAMPLE: CIC::DUX4 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| EXAMPLE: ALK | EXAMPLE: ELM4::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). | |
| EXAMPLE: ABL1 | EXAMPLE: N/A | EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. | EXAMPLE: N/A | EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) | EXAMPLE: D, P, T | ||
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.
No chromosome rearrangements specifically associated with CMML.
By definition, the presence of BCR-ABL11 or rearrangements involving PDGFRA, PDGFRB or FGFR1 and PCM1-JAK2 defines categories other than CMML.
End of V4 Section
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)
Presence of one or more mutations, especially concurrent mutations in TET2 and SRSF2 is very helpful for a definitive diagnosis.
Survival times range from 1 month to > 100 months; the median survival time in most series is 20-40 months[1][2][3][4].
15- 30% of cases progress to acute myeloid leukemia (AML), classified as AML with myelodysplasia-related changes (MRC).
Important factors predicting progression and survival time[3]:
- Percentage of blasts in blood and bone marrow is the most important factor determining survival
- Karyotype, ASXL1 mutation[5]
- Leukocytosis
Other predictive factors for disease progression:
- Lactate dehydrogenase (LDH) level
- Splenomegaly
- Anemia, thrombocytopenia and lymphocytosis (>2.5 x 109/L)
Somatic ASXL1 mutation has also been incorporated in a clinical prognostic scoring system[5].
End of V4 Section
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: 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 references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.
Clonal cytogenetic abnormalities are found in 20-40% of CMML cases, but there are no specific abnormalities[6].
| Chromosomal Abnormality | Prevalence |
|---|---|
| Trisomy 8 | up to 10% |
| del(20q) | up to 10% |
| -Y | 4% |
| -7 or del(7q) | 1.5% |
| Complex | 3% |
End of V4 Section
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.
No characteristic chromosome aberrations identified in association with CMML.
End of V4 Section
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.
Over 90% of CMML patients studied exhibited one or more mutations[7]. Concurrent mutations in TET2 and SRSF2 appear to be highly specific for this entity[8][9]. Mutations in certain pathways correlated with clinical classification (dysplastic vs. proliferative)[10].
| Gene | Mutation | Prevalence[7][8] |
|---|---|---|
| TET2 | 50-60% | |
| SRSF2 | 40-50% | |
| ASXL1 | 35-40% | |
| RUNX1 | 15-25%, usually secondary[11] | |
| NRAS | p.G12 most common | 11% |
| CBL | 10% | |
| JAK2 | V617F | 10% |
| NOTCH | 10% |
Other Mutations
| Type | Gene/Region/Other |
|---|---|
| Mutation prevalence not well studied in | PTPN11, DNMT3A, IDH2, IDH1, SF3B1,U2AF35, ZRSR2, UTX, EZH2,
KRAS, CBL, CSF3R, SETBP1 |
| Uncommon Mutations in | NPM1, CEBPA, FLT3-ITD, TP53 |
The clonal evolution and secondary subclonal hierarchy may be correlated with clinical phenotypes or outcomes[10].
End of V4 Section
Epigenomic Alterations
The genome-wide methylation profiles showed limited applicability in a diagnostic setting[12][13].
The methylation level of individual selected gene promoters have been correlated with overall survival (OS) and progression free survival (PFS)[13]:
- CDH1, ETS1, DAXX, FADD, DAPP1, AATK, CYFIP, TP53, BP2, and AIM2, which were hypermethylated in CMML samples.
- BCL2 hypomethylation is predictive of poorer OS and PFS.
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)
| 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 |
Genetic Diagnostic Testing Methods
- Blood cell counts and smear review.
- Bone marrow aspirate and core biopsy with flow cytometric immunophenotyping and immunohistochemical stains.
- Molecular genetic studies are essential to provide clonal evidence for a diagnosis of a myeloid neoplasm, and rule out other well defined entities.
- There are no diagnostic molecular/genetic abnormalities specific for CMML.
Familial Forms
Familial form of CMML has not been reported.
A patient with CMML secondary to familial platelet disorder with germline RUNX1 mutation (classified as myeloid neoplasm with germline RUNX1 mutation) was reported after acquired CBL mutation and 11q-acquired uniparental disomy (11q-aUPD)[14].
Additional Information
Acute myeloid leukemia (AML) with monocytic differentiation frequently have increased circulating mature monocytes (more mature forms than in the bone marrow), the final diagnosis of CML should never be rendered without an evaluation of BM to rule out acute myeloid leukemia. Rarely, CMML can be "marrow-predominant", with monocytes largely confined to the BM without showing absolute monocytosis[15].
Links
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References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
- ↑ Longuet, Christine; et al. (2008). "The glucagon receptor is required for the adaptive metabolic response to fasting". Cell metabolism. 8 (5): 359–371. doi:10.1016/j.cmet.2008.09.008. ISSN 1550-4131. PMC 2593715. PMID 19046568.
- ↑ Nijagal, Amar; et al. (2011). "The maternal immune response inhibits the success of in utero hematopoietic cell transplantation". Chimerism. 2 (2): 55–57. doi:10.4161/chim.2.2.16287. ISSN 1938-1956. PMC 3166485. PMID 21912720.
- ↑ Jump up to: 3.0 3.1 U, Germing; et al. (2004). "Risk Assessment in Chronic Myelomonocytic Leukemia (CMML)". PMID 15359628.
- ↑ A, Worsley; et al. (1988). "Prognostic Features of Chronic Myelomonocytic Leukaemia: A Modified Bournemouth Score Gives the Best Prediction of Survival". PMID 3422815.
- ↑ Jump up to: 5.0 5.1 R, Itzykson; et al. (2013). "Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia". PMID 23690417.
- ↑ Such, E.; et al. (2011). "Cytogenetic risk stratification in chronic myelomonocytic leukemia". Haematologica. 96 (3): 375–383. doi:10.3324/haematol.2010.030957. ISSN 0390-6078. PMC 3046268. PMID 21109693.CS1 maint: PMC format (link)
- ↑ Jump up to: 7.0 7.1 Arber DA, et al., (2017). Introduction and overview of the classification of myeloid neoplasms, 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, Editors. IARC Press: Lyon, France, p82-86.
- ↑ Jump up to: 8.0 8.1 Ti, Mughal; et al. (2015). "An International MDS/MPN Working Group's Perspective and Recommendations on Molecular Pathogenesis, Diagnosis and Clinical Characterization of Myelodysplastic/Myeloproliferative Neoplasms". doi:10.3324/haematol.2014.114660. PMC 4800699. PMID 26341525.CS1 maint: PMC format (link)
- ↑ Gelsi-Boyer, Véronique; et al. (2008). "Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes". BMC Cancer. 8 (1). doi:10.1186/1471-2407-8-299. ISSN 1471-2407. PMC 2588460. PMID 18925961.CS1 maint: PMC format (link)
- ↑ Jump up to: 10.0 10.1 Patel, B J; et al. (2017). "Genomic determinants of chronic myelomonocytic leukemia". Leukemia. 31 (12): 2815–2823. doi:10.1038/leu.2017.164. ISSN 0887-6924.
- ↑ Palomo, Laura; et al. (2020). "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms". Blood. doi:10.1182/blood.2019004229. ISSN 0006-4971.
- ↑ Deininger, Michael W.; et al. (2018). "Molecular Alterations in Chronic Myelomonocytic Leukemia Monocytes: Transcriptional and Methylation Profiling". Blood. 132 (Supplement 1): 3889–3889. doi:10.1182/blood-2018-99-115077. ISSN 0006-4971.
- ↑ Jump up to: 13.0 13.1 Palomo, Laura; et al. (2018). "DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features". Epigenetics. 13 (1): 8–18. doi:10.1080/15592294.2017.1405199. ISSN 1559-2294. PMC 5837079. PMID 29160764.CS1 maint: PMC format (link)
- ↑ Shiba, Norio; et al. (2012). "CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML)". Blood. 119 (11): 2612–2614. doi:10.1182/blood-2011-02-333435. ISSN 0006-4971.
- ↑ A, Orazi; et al. (2008). "The Myelodysplastic/Myeloproliferative Neoplasms: Myeloproliferative Diseases With Dysplastic Features". PMID 18480833.
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 Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
*Citation of this Page: “Chronic myelomonocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Chronic_myelomonocytic_leukaemia.