Chronic neutrophilic leukaemia
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
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 Neutrophilic Leukemia (CNL).
(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)*
Anamaria Munteanu, MD, Ph.D**, Harbor-UCLA Medical Center, Joseph J. Merlo Jr, MD. Ph.D**, Ashion Analytics, Fabiola Quintero-Rivera, University of California Irvine
**contributed equally
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Myeloproliferative neoplasms |
| Type | Myeloproliferative neoplasms |
| Subtype(s) | Chronic neutrophilic 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.
CNL is by definition Philadelphia chromosome negative (BCR/ABL1-negative).[1]
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| t(15;19)(q13;q13.3) | rare |
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)
CNL can progress to myeloma or blastic transformation to acute myeloid leukemia.[2] It can also transform in other forms of MPN (PV or CMML). The presence of ASXL1 as secondary mutation confers worse prognosis.[1][3]
Thrombocytopenia also proves to be an adverse prognostic factor. Patients with CNL have a hemorrhagic tendency, leading to cerebral hemorrhage as the most significant registered cause of death.[4] Other causes of death include generalized leukemic tissue infiltration, ileus caused by a granulocytic and myelocytic infiltration of the small bowel, and pneumonia.[5]
Treatment: There is currently no standard of care or established guidelines for the management of CNL. As such, treatment may involve several therapeutic approaches.[6] Blood transfusions when necessary, hydroxyurea, allogeneic bone marrow transplantation. Clinical remission has been achieved in instances with long-term interferon α treatment.[5] Hydroxyurea is the most used therapy, but often requires a second or third line therapy.[6][7][8] Other potential pharmacologic agents include imatinib, ruxolitinib, interferon-alpha(IFN-α), hypomethylating agents, thalidomide, and cladribine. These may be used in combination.[8][6][9][10] Cases with CSF3R T618I mutation may respond to treatment with Ruxolitinib (JAK inhibitor) while cases with CSF3R truncation mutations may be sensitive to Dasatinib (SRC kinase inhibitor).[2]
The presenting features may be non-specific with organomegaly involving the liver, spleen or both, mucocutaneous bleeding, and bruising.[1] The disease has a variable prognosis with some cases rapidly evolving[8][11]; others may have an indolent course spanning decades.[12] Survival is variable, overall mean survival being between 21-30 months.
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. | |
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.
Karyotypic abnormalities occur in ~10% of cases while 90% of CNL cases demonstrate a normal karyotype.[1][2] There are no diagnostic gains, chromosome losses or losses of heterozygosity (LOH) associated with CNL.
Non-specific gains of 8 (most frequent), 9, and 21.
Losses have been reported including del(7q), del(20q) (most frequent), del(11q) or 12p.
Sometimes a complex karyotype is present.
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.
CNL has been strongly associated with mutations in CSF3R.[6][13] Two types of CSF3R mutations have been described. The first is a missense mutation involving the juxta-membrane region (e.g. T618I, the most common CSF3R mutation in CNL). The other results in a nonsense or frameshift mutation leading to a truncated protein and subsequent loss of the C-terminus tail region (e.g. CSF3R D771fs, S783 fs, Y752X, and W791Z).[6][13] CNL can also be associated with several genes involved in mRNA splicing, epigenetic modifications, and signaling proteins. Notably, mutations in SETBP1 and ASXL1 have been described as frequent co-occurrences in association with mutated CSF3R.[13][3] Less frequently, concurrent JAK2 mutations have also been identified with mutated CSF3R.[1][6][13][3]
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| CSF3R | T618I, T615A,
truncation[13] |
|||
| JAK2 | V617F |
Other Mutations
SETBP1, ASXL1, TET2, SRSF2, U2AF1, CALR
| Type | Gene/Region/Other |
|---|---|
| Concomitant Mutations | CSF3R and SETBP1, CSF3R AND ASXL1 |
| Mutually Exclusive | JAK2 V617F and CSF3R T618I |
End of V4 Section
Epigenomic Alterations
Put your text here
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 |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.
Colony-stimulating factor 3 receptor (CSF3R) is a gene located on chromosome 1p34.3 encoding the cytokine receptor for granulocyte colony-stimulating factor (G-CSF) or otherwise known as colony-stimulating factor 3 (CSF 3). Its binding activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinases, and PI3K/Akt pathways; CSF3R has been shown to signal through the JAK–STAT pathway, the nonreceptor tyrosine kinase SYK, and the SRC family kinase LYN.[14][15] In bone marrow it stimulates granulopoesis by inducing proliferation and differentiation of precursor cells into mature granulocytes.[2]
End of V4 Section
Genetic Diagnostic Testing Methods
Gene sequencing, karyotype, peripheral blood smear, flow cytometry, bone marrow biopsy, FISH, NGS.[1]
Familial Forms
No familial forms have been described.
Additional Information
Put your text here
Links
SEER Hematopoietic and Lymphoid Neoplasm Database; Chronic Neutrophilic Leukemia
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.)
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Bain BJ, et al., (2017). Chronic Neutrophilic Leukaemia, 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, p37-38.
- ↑ 2.0 2.1 2.2 2.3 N, Szuber; et al. (2018). "Chronic neutrophilic leukemia: new science and new diagnostic criteria". doi:10.1038/s41408-018-0049-8. PMC 5811432. PMID 29440636.CS1 maint: PMC format (link)
- ↑ 3.0 3.1 3.2 Ma, Elliott; et al. (2015). "ASXL1 mutations are frequent and prognostically detrimental in CSF3R-mutated chronic neutrophilic leukemia". PMID 25850813.
- ↑ T, Mitsumori; et al. (2016). "A CSF3R T618I Mutation in a Patient with Chronic Neutrophilic Leukemia and Severe Bleeding Complications". PMID 26875968.
- ↑ 5.0 5.1 J, Böhm; et al. (2002). "Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease". doi:10.1136/jcp.55.11.862. PMC 1769801. PMID 12401827.CS1 maint: PMC format (link)
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Szuber, Natasha; et al. (02 2020). "Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management". American Journal of Hematology. 95 (2): 212–224. doi:10.1002/ajh.25688. ISSN 1096-8652. PMID 31769070. Check date values in:
|date=(help) - ↑ Elliott, M. A.; et al. (2005-02). "WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature". Leukemia. 19 (2): 313–317. doi:10.1038/sj.leu.2403562. ISSN 0887-6924. PMID 15549147. Check date values in:
|date=(help) - ↑ 8.0 8.1 8.2 Silva, Patrícia Rocha; et al. (2015-06). "Diagnosis, complications and management of chronic neutrophilic leukaemia: A case report". Oncology Letters. 9 (6): 2657–2660. doi:10.3892/ol.2015.3148. ISSN 1792-1074. PMC 4473643. PMID 26137123. Check date values in:
|date=(help) - ↑ Dao, Kim-Hien T.; et al. (2020-04-01). "Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 38 (10): 1006–1018. doi:10.1200/JCO.19.00895. ISSN 1527-7755. PMC 7106977 Check
|pmc=value (help). PMID 31880950. - ↑ Gunawan, Arief S.; et al. (06 2017). "Ruxolitinib, a potent JAK1/JAK2 inhibitor, induces temporary reductions in the allelic burden of concurrent CSF3R mutations in chronic neutrophilic leukemia". Haematologica. 102 (6): e238–e240. doi:10.3324/haematol.2017.163790. ISSN 1592-8721. PMC 5451352. PMID 28302714. Check date values in:
|date=(help) - ↑ Zittoun, R.; et al. (1994-02). "Chronic neutrophilic leukemia. A study of four cases". Annals of Hematology. 68 (2): 55–60. doi:10.1007/BF01715131. ISSN 0939-5555. PMID 8148416. Check date values in:
|date=(help) - ↑ Uppal, Guldeep; et al. (2015-09). "Chronic neutrophilic leukaemia". Journal of Clinical Pathology. 68 (9): 680–684. doi:10.1136/jclinpath-2015-203060. ISSN 1472-4146. PMID 26082513. Check date values in:
|date=(help) - ↑ 13.0 13.1 13.2 13.3 13.4 Je, Maxson; et al. (2013). "Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML". doi:10.1056/NEJMoa1214514. PMC 3730275. PMID 23656643.CS1 maint: PMC format (link)
- ↑ Corey, S. J.; et al. (1998-02-06). "Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor". The Journal of Biological Chemistry. 273 (6): 3230–3235. doi:10.1074/jbc.273.6.3230. ISSN 0021-9258. PMID 9452436.
- ↑ Corey, S. J.; et al. (1994-05-24). "Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases". Proceedings of the National Academy of Sciences of the United States of America. 91 (11): 4683–4687. doi:10.1073/pnas.91.11.4683. ISSN 0027-8424. PMC 43852. PMID 8197119.CS1 maint: PMC format (link)
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 neutrophilic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Chronic_neutrophilic_leukaemia.