View source for HAEM4:Chronic Neutrophilic Leukemia (CNL)

{{DISPLAYTITLE:Chronic Neutrophilic Leukemia (CNL)}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
==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

<nowiki>**</nowiki>contributed equally

__TOC__

==Cancer Category/Type==

[[HAEM4:Myeloproliferative Neoplasms (MPN)|Myeloproliferative Neoplasms]]

==Cancer Sub-Classification / Subtype==

Chronic neutrophilic leukemia

==Definition / Description of Disease==

Chronic neutrophilic leukemia (CNL) is a rare heterogeneous BCR/ABL1-negative member of the WHO myeloproliferative neoplasm (MPN) category, which presents with neutrophilia lacking dysplastic features.  Diagnostic criteria include sustained increased white blood cells in the peripheral blood for more than 3 months, with a predominance of band and segmented forms equal to or in excess of 25 x10<sup>9</sup>/L.<ref name=":0" />  The bone marrow is hypercellular with elevated myeloid to erythroid ratio, due to increase in neutrophilic granulocyte proliferation, with normal maturation (>80% mature forms of neutrophils and <10% neutrophil precursors) and rare (<5%) of nucleated cells represented by myeloblasts.  This disease is also associated with hepatosplenomegaly, but can affect other tissues.

Diagnosis is made after exclusion of reactive neutrophilia (especially due to plasma cell neoplasms), atypical CML and of other myeloproliferative neoplasms ([[HAEM5:Chronic myeloid leukaemia|BCR-ABL1- positive Chronic Myeloid Leukemia]], [[HAEM5:Polycythaemia vera|Polycythemia Vera]], [[HAEM5:Essential thrombocythaemia|Essential Thrombocythemia]] and [[HAEM5:Primary myelofibrosis|Primary Myelofibrosis]]) and and myelodysplastic syndrome/myeloproliferative neoplasms.<ref name=":0" /><ref name=":3">{{Cite journal|last=Szuber|first=Natasha|last2=Elliott|first2=Michelle|last3=Tefferi|first3=Ayalew|date=02 2020|title=Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management|url=https://pubmed.ncbi.nlm.nih.gov/31769070|journal=American Journal of Hematology|volume=95|issue=2|pages=212–224|doi=10.1002/ajh.25688|issn=1096-8652|pmid=31769070}}</ref><ref name=":4" />  Previous use of G-CSF and leukaemogenic drugs (busulphan, melphalan) must also be excluded.

Mutations in ''CSF3R'' (colony-stimulating factor 3 receptor) are present in the majority of CNL cases and are part of diagnostic criteria. Genetic rearrangement for ''PDGFRA'', ''PDGFRB'', ''FGFR1'', and ''PCM1''-''JAK2'' fusion must be absent.<ref name=":0">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.</ref>
==Synonyms / Terminology==

CNL

==Epidemiology / Prevalence==

CNL is a rare disease with the true incidence being unknown.  While >200 cases were previously reported, three quarters to half of these do not meet current guidelines for a diagnosis of chronic neutrophilic leukemia<ref name=":0" /><ref name=":1">{{Cite journal|last=N|first=Szuber|last2=A|first2=Tefferi|date=2018|title=Chronic neutrophilic leukemia: new science and new diagnostic criteria|url=https://pubmed.ncbi.nlm.nih.gov/29440636/|language=en|doi=10.1038/s41408-018-0049-8|pmc=PMC5811432|pmid=29440636}}</ref>  Evidence suggests that CNL is extremely rare with one report investigating chronic leukemias of myeloid origin finding less than 1/660 cases meeting criteria for establishing the diagnosis.<ref name=":4" /><ref name=":5">{{Cite journal|last=Elliott|first=M. A.|last2=Hanson|first2=C. A.|last3=Dewald|first3=G. W.|last4=Smoley|first4=S. A.|last5=Lasho|first5=T. L.|last6=Tefferi|first6=A.|date=2005-02|title=WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature|url=https://pubmed.ncbi.nlm.nih.gov/15549147|journal=Leukemia|volume=19|issue=2|pages=313–317|doi=10.1038/sj.leu.2403562|issn=0887-6924|pmid=15549147}}</ref>  

Differential diagnosis of CNL includes neutrophilic leukemoid reaction associated with secretion of granulocyte stimulating factor by plasma cells in Multiple Myeloma or MGUS. Median age at presentation is 66 years old, with a nearly equal, slightly higher female to male prevalence.

==Clinical Features==

Most patients are asymptomatic, but sometimes present with fatigue. Constitutional symptoms may be present at diagnosis, including weight loss, and night sweats. Sometimes bruising, pruritus, or gout. A common clinical manifestation is hepatosplenomegaly. 

Blood analysis can show elevated values for LDH, leukocyte alkaline phosphatase (LAP), serum vitamin B12, and uric acid.

==Sites of Involvement==

Peripheral blood and bone marrow involvement are consistently present.  The spleen and liver are two of the most involved extramedullary sites with splenomegaly and/or hepatomegaly resulting from infiltrating neutrophils.<ref name=":0" /><ref name=":3" /><ref name=":6">{{Cite journal|last=Silva|first=Patrícia Rocha|last2=Ferreira|first2=Cristina|last3=Bizarro|first3=Susana|last4=Cerveira|first4=Nuno|last5=Torres|first5=Lurdes|last6=Moreira|first6=Ilídia|last7=Mariz|first7=José Mário|date=2015-06|title=Diagnosis, complications and management of chronic neutrophilic leukaemia: A case report|url=https://pubmed.ncbi.nlm.nih.gov/26137123|journal=Oncology Letters|volume=9|issue=6|pages=2657–2660|doi=10.3892/ol.2015.3148|issn=1792-1074|pmc=4473643|pmid=26137123}}</ref>  However, the disease can affect virtually any tissue type. 

==Morphologic Features==

Peripheral Blood: typically persistent leukocytosis >3 months with white blood cells composed predominantly of bands and segmented neutrophils exceeding or equaling 80% of white blood cells.  The neutrophils have frequent Dohle bodies, sometimes vacuolation and hypersegmentation <ref name=":4">{{Cite journal|last=Bj|first=Bain|last2=S|first2=Ahmad|date=2015|title=Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions|url=https://pubmed.ncbi.nlm.nih.gov/26218186/|language=en|pmid=26218186}}</ref>. Toxic granulation may be present.  Most CNL patients also have mild anemia and thrombocytopenia <ref name=":1" />

Bone marrow: hypercellularity with elevated myeloid to erythroid ratio (often > 10:1), due to increase in neutrophilic granulocyte proliferation, with normal maturation and minimal to absent dysplastic changes. Ingestion of neutrophils by macrophages can be seen.  Erythroid lineage and megakaryocytes are normal.  Less than 5% of nucleated cells are myeloblasts.<ref>Chronic Neutrophilic Leukemia  in Bone Marrow Pathology. Kathryn Foucar, Kaaren Reichard, David Czuchlewski, ASCP Press, 2020, p284-288.</ref>  The development of dysplastic features may herald disease progression or transformation to acute myeloid leukemia.<ref name=":0" /><ref name=":6" />
==Immunophenotype==

There is no specific immunophenotype.<ref name=":0" />

==Chromosomal Rearrangements (Gene Fusions)==
CNL is by definition Philadelphia chromosome negative (BCR/ABL1-negative).<ref name=":0" />  
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(15;19)(q13;q13.3)|| || ||rare
|}		
			
==Characteristic Chromosomal Aberrations / Patterns==

Karyotypic abnormalities occur in ~10% of cases while 90% of CNL cases demonstrate a normal karyotype.<ref name=":0" /><ref name=":1" />  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.

==Genomic Gain/Loss/LOH==

Put your text here
==Gene Mutations (SNV/INDEL)==

CNL has been strongly associated with mutations in ''CSF3R''.<ref name=":3" /><ref name=":7" />  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).<ref name=":3" /><ref name=":7" />   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''.<ref name=":7" /><ref name=":8" />  Less frequently, concurrent ''JAK2'' mutations have also been identified with mutated ''CSF3R''.<ref name=":0" /><ref name=":3" /><ref name=":7" /><ref name=":8" />

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|''CSF3R''||T618I, T615A,
truncation<ref name=":7">{{Cite journal|last=Je|first=Maxson|last2=J|first2=Gotlib|last3=Da|first3=Pollyea|last4=Ag|first4=Fleischman|last5=A|first5=Agarwal|last6=Ca|first6=Eide|last7=D|first7=Bottomly|last8=B|first8=Wilmot|last9=Sk|first9=McWeeney|date=2013|title=Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML|url=https://pubmed.ncbi.nlm.nih.gov/23656643/|language=en|doi=10.1056/NEJMoa1214514|pmc=PMC3730275|pmid=23656643}}</ref>
| || ||
|-
|''JAK2''
|V617F
|
|
|
|}	
		
===Other Mutations===
''SETBP1'', ''ASXL1'', ''TET2'', ''SRSF2'', ''U2AF1'', ''CALR''
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||''CSF3R'' and ''SETBP1'', ''CSF3R'' AND ''ASXL1''
|-
|Mutually Exclusive||''JAK2'' V617F and ''CSF3R'' T618I
|}

==Epigenomics (Methylation)==

Put your text here

==Genes and Main Pathways Involved==

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''.<ref>{{Cite journal|last=Corey|first=S. J.|last2=Dombrosky-Ferlan|first2=P. M.|last3=Zuo|first3=S.|last4=Krohn|first4=E.|last5=Donnenberg|first5=A. D.|last6=Zorich|first6=P.|last7=Romero|first7=G.|last8=Takata|first8=M.|last9=Kurosaki|first9=T.|date=1998-02-06|title=Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor|url=https://pubmed.ncbi.nlm.nih.gov/9452436|journal=The Journal of Biological Chemistry|volume=273|issue=6|pages=3230–3235|doi=10.1074/jbc.273.6.3230|issn=0021-9258|pmid=9452436}}</ref><ref>{{Cite journal|last=Corey|first=S. J.|last2=Burkhardt|first2=A. L.|last3=Bolen|first3=J. B.|last4=Geahlen|first4=R. L.|last5=Tkatch|first5=L. S.|last6=Tweardy|first6=D. J.|date=1994-05-24|title=Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases|url=https://pubmed.ncbi.nlm.nih.gov/8197119|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=91|issue=11|pages=4683–4687|doi=10.1073/pnas.91.11.4683|issn=0027-8424|pmc=PMC43852|pmid=8197119}}</ref>  In bone marrow it stimulates granulopoesis by inducing proliferation and differentiation of precursor cells into mature granulocytes.<ref name=":1" />
==Diagnostic Testing Methods==

Gene sequencing, karyotype, peripheral blood smear, flow cytometry, bone marrow biopsy, FISH, NGS.<ref name=":0" />

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

CNL can progress to myeloma or blastic transformation to acute myeloid leukemia.<ref name=":1" />  It can also transform in other forms of MPN (PV or CMML). The presence of ''ASXL1'' as secondary mutation confers worse prognosis.<ref name=":0" /><ref name=":8">{{Cite journal|last=Ma|first=Elliott|last2=A|first2=Pardanani|last3=Ca|first3=Hanson|last4=Tl|first4=Lasho|last5=Cm|first5=Finke|last6=Aa|first6=Belachew|last7=A|first7=Tefferi|date=2015|title=ASXL1 mutations are frequent and prognostically detrimental in CSF3R-mutated chronic neutrophilic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/25850813/|language=en|pmid=25850813}}</ref>

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.<ref>{{Cite journal|last=T|first=Mitsumori|last2=N|first2=Komatsu|last3=K|first3=Kirito|date=2016|title=A CSF3R T618I Mutation in a Patient with Chronic Neutrophilic Leukemia and Severe Bleeding Complications|url=https://pubmed.ncbi.nlm.nih.gov/26875968/|language=en|pmid=26875968}}</ref>  Other causes of death include generalized leukemic tissue infiltration, ileus caused by a granulocytic and myelocytic infiltration of the small bowel, and pneumonia.<ref name=":2">{{Cite journal|last=J|first=Böhm|last2=He|first2=Schaefer|date=2002|title=Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease|url=https://pubmed.ncbi.nlm.nih.gov/12401827/|language=en|doi=10.1136/jcp.55.11.862|pmc=PMC1769801|pmid=12401827}}</ref> 

Treatment: There is currently no standard of care or established guidelines for the management of CNL. As such, treatment may involve several therapeutic approaches.<ref name=":3" />  Blood transfusions when necessary, hydroxyurea, allogeneic bone marrow transplantation. Clinical remission has been achieved in instances with long-term interferon α treatment.<ref name=":2" />  Hydroxyurea is the most used therapy, but often requires a second or third line therapy.<ref name=":3" /><ref name=":5" /><ref name=":6" />  Other potential pharmacologic agents include imatinib, ruxolitinib, interferon-alpha(IFN-α), hypomethylating agents, thalidomide, and cladribine.  These may be used in combination.<ref name=":6" /><ref name=":3" /><ref>{{Cite journal|last=Dao|first=Kim-Hien T.|last2=Gotlib|first2=Jason|last3=Deininger|first3=Michael M. N.|last4=Oh|first4=Stephen T.|last5=Cortes|first5=Jorge E.|last6=Collins|first6=Robert H.|last7=Winton|first7=Elliot F.|last8=Parker|first8=Dana R.|last9=Lee|first9=Hyunjung|date=2020-04-01|title=Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/31880950|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=38|issue=10|pages=1006–1018|doi=10.1200/JCO.19.00895|issn=1527-7755|pmc=7106977|pmid=31880950}}</ref><ref>{{Cite journal|last=Gunawan|first=Arief S.|last2=McLornan|first2=Donal P.|last3=Wilkins|first3=Bridget|last4=Waghorn|first4=Katherine|last5=Hoade|first5=Yvette|last6=Cross|first6=Nicholas C. P.|last7=Harrison|first7=Claire N.|date=06 2017|title=Ruxolitinib, a potent JAK1/JAK2 inhibitor, induces temporary reductions in the allelic burden of concurrent CSF3R mutations in chronic neutrophilic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28302714|journal=Haematologica|volume=102|issue=6|pages=e238–e240|doi=10.3324/haematol.2017.163790|issn=1592-8721|pmc=5451352|pmid=28302714}}</ref>  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).<ref name=":1" />

The presenting features may be non-specific with organomegaly involving the liver, spleen or both, mucocutaneous bleeding, and bruising.<ref name=":0" />  The disease has a variable prognosis with some cases rapidly evolving<ref name=":6" /><ref>{{Cite journal|last=Zittoun|first=R.|last2=Réa|first2=D.|last3=Ngoc|first3=L. H.|last4=Ramond|first4=S.|date=1994-02|title=Chronic neutrophilic leukemia. A study of four cases|url=https://pubmed.ncbi.nlm.nih.gov/8148416|journal=Annals of Hematology|volume=68|issue=2|pages=55–60|doi=10.1007/BF01715131|issn=0939-5555|pmid=8148416}}</ref>; others may have an indolent course spanning decades.<ref>{{Cite journal|last=Uppal|first=Guldeep|last2=Gong|first2=Jerald|date=2015-09|title=Chronic neutrophilic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/26082513|journal=Journal of Clinical Pathology|volume=68|issue=9|pages=680–684|doi=10.1136/jclinpath-2015-203060|issn=1472-4146|pmid=26082513}}</ref>  Survival is variable, overall mean survival being between 21-30 months.
==Familial Forms==

No familial forms have been described.

==Other Information==

Put your text here

==Links==

[https://seer.cancer.gov/seertools/hemelymph/51f6cf58e3e27c3994bd5402/ SEER Hematopoietic and Lymphoid Neoplasm Database; Chronic Neutrophilic Leukemia]

==References==
<references />

==Notes==
<nowiki>*</nowiki>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.
[[Category:HAEM4]] [[Category:DISEASE]]