Chronic Neutrophilic Leukemia (CNL)
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
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 x109/L. 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 (BCR-ABL1- positive Chronic Myeloid Leukemia, Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis) and and myelodysplastic syndrome/myeloproliferative neoplasms. 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.
Synonyms / Terminology
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 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.
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.
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. However, the disease can affect virtually any tissue type.
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 . Toxic granulation may be present. Most CNL patients also have mild anemia and thrombocytopenia 
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. The development of dysplastic features may herald disease progression or transformation to acute myeloid leukemia.
There is no specific immunophenotype.
Chromosomal Rearrangements (Gene Fusions)
CNL is by definition Philadelphia chromosome negative (BCR/ABL1-negative).
|Chromosomal Rearrangement||Genes in Fusion (5’ or 3’ Segments)||Pathogenic Derivative||Prevalence|
Characteristic Chromosomal Aberrations / Patterns
Karyotypic abnormalities occur in ~10% of cases while 90% of CNL cases demonstrate a normal karyotype. 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.
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Gene Mutations (SNV/INDEL)
CNL has been strongly associated with mutations in CSF3R. 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). 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. Less frequently, concurrent JAK2 mutations have also been identified with mutated CSF3R.
|Gene||Mutation||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
SETBP1, ASXL1, TET2, SRSF2, U2AF1, CALR
|Concomitant Mutations||CSF3R and SETBP1, CSF3R AND ASXL1|
|Mutually Exclusive||JAK2 V617F and CSF3R T618I|
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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. In bone marrow it stimulates granulopoesis by inducing proliferation and differentiation of precursor cells into mature granulocytes.
Diagnostic Testing Methods
Gene sequencing, karyotype, peripheral blood smear, flow cytometry, bone marrow biopsy, FISH, NGS.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
CNL can progress to myeloma or blastic transformation to acute myeloid leukemia. It can also transform in other forms of MPN (PV or CMML). The presence of ASXL1 as secondary mutation confers worse prognosis.
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. Other causes of death include generalized leukemic tissue infiltration, ileus caused by a granulocytic and myelocytic infiltration of the small bowel, and pneumonia.
Treatment: There is currently no standard of care or established guidelines for the management of CNL. As such, treatment may involve several therapeutic approaches. Blood transfusions when necessary, hydroxyurea, allogeneic bone marrow transplantation. Clinical remission has been achieved in instances with long-term interferon α treatment. Hydroxyurea is the most used therapy, but often requires a second or third line therapy. Other potential pharmacologic agents include imatinib, ruxolitinib, interferon-alpha(IFN-α), hypomethylating agents, thalidomide, and cladribine. These may be used in combination. 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).
The presenting features may be non-specific with organomegaly involving the liver, spleen or both, mucocutaneous bleeding, and bruising. The disease has a variable prognosis with some cases rapidly evolving; others may have an indolent course spanning decades. Survival is variable, overall mean survival being between 21-30 months.
No familial forms have been described.
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