At a Glance

Chronic Neutrophilic Leukemia (CNL) is a vanishingly rare disease (less than 1% of chronic myeloproliferative neoplasia (CMPN)) characterized by a persistent leukocytosis greater than 25,000/μl comprised of more than 80% segmented neutrophils and bands. There must be less than 10% immature myeloids and less than 1% myeloblasts in the peripheral blood and less than 5% blasts in the bone marrow. Most CNL patients present with hepatosplenomegaly.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Karyotype and Fluorescent In Situ Hybridization (FISH) for BCRABL should be ordered to rule out chronic myelogenous leukemia (CML). CNL must lack the Philadelphia chromosome and the BCRABL fusion gene. The CMPN associated with the p230 BCRABL protein previously classified as CNL is now considered neutrophil-rich CML to encourage the use of tyrosine kinase inhibitors in its therapy. Suspected cases for CNL must also lack dysplasia, monocytosis, and JAK2 mutations. Cases that would be better classified as myelodysplasia (MDS), chronic myelomonocytic leukemia (CMML), primary myelofibrosis (PMF), essential thrombocythemia (ET), polycythemia vera (PV), or CMPN, Unclassifiable should be classified as such, rather than as CNL.

JAK2V617F should be performed to rule out other CMPN.

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Bone marrow biopsy should be performed to confirm myeloproliferation without features of any other MDS, CMPD, or MDS/CMPD. Karyotype is normal in 80-90% of CNL patients with +8, +9, del(11q23) and del(20q) being found in the remainder.

Without evidence of clonality in the neutrophils, the exclusion of secondary causes for neutrophilia is paramount. Solid tumors, plasma cell dyscrasias, chronic infections, and inflammatory diseases can all cause secondary neutrophilia that should not be classified as CNL.

Hepatosplenomegaly is a common finding in CNL patients.

Test Results Indicative of the Disorder

World Health Organization (WHO) 2008 diagnostic criteria for CNL include:

No evidence of MDS or MPN/MDS, such as increased monocytes or dysplasia in any of the lineages

White blood cell count (WBC) greater than or equal to 25,000/microliter that is composed of more than 80% segmented neutrophils and bands with immature myeloids (metamyelocytes, myelocytes and promyelocytes) comprising less than 10% of WBC

Blasts less than 1% of WBC in peripheral blood and less than 5% in bone marrow

Hypercellular bone marrow biopsy with increased neutrophils showing no overt dysplasia, normal megakaryocytes


No reactive cause for neutrophilia (i.e., no infections, no inflammatory process/autoimmune disease, no coexistent tumor) or proven clonality in the neutrophils using cytogenetics or molecular genetics

No BCRABL fusion, no rearrangements of PDGFRα, PDGFRβ or FGFR1

No evidence of PV, PMF or ET

What Lab Results Are Absolutely Confirmatory?

CNL has no absolutely confirmatory testing, but rather relies on a constellation of lab results together, particularly negative lab results to rule out other causes of neutrophilia as CNL is primarily a diagnosis of exclusion. The primary features of the diagnosis are to ensure the patient who meets the complete blood count-based (CBC-based) criteria does not fit into 1 of the other categories of disease.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

If the patient does meet all criteria for CNL and does not meet criteria for any other myeloproliferative or myelodysplastic disease, a careful examination for myeloma or other tumors should be undertaken. Twenty percent of all cases of CNL have occurred concurrent with a plasma cell dyscrasia. Of note, if a clonal plasmacytosis or monoclonal gammopathy of uncertain significance (MGUS) is detected, the neutrophilia must be shown to be clonal before a diagnosis of CNL can be made as reactive neutrophilia have been described in plasma cell dyscrasias.

Are There Any Factors That Might Affect the Lab Results?

Detection of the BCRABL fusion gene is diagnostic of CML and inconsistent with the diagnosis of CNL. Although most translocations can be detected by classical G-banding karyotype, some cryptic translocations can only be detected by FISH. Polymerase chain reaction (PCR) for BCRABL is more sensitive than FISH but may not detect all isoforms of the BCRABL protein. In particular, most PCR-based testing for BCRABL will detect the p210 isoform common in CML and may detect the p190 isoform often found in acute lymphoblastic leukemia (ALL) P190 and p210 BCRABL. PCR will not always detect the p230 isoform associated with neutrophil-rich variant of CML. Therefore, in Philadelphia chromosome-negative neutrophil-rich CMPN, a FISH for BCRABL is recommended to rule out p230 CML.

What is the Prognosis for the Disorder?

There are no large studies of CNL due to its rarity. In those cases examined, there is a wide range of survival, from 6 months to more than 20 years. Development of AML can occur, particularly if dysplasia develops. Other features of bone marrow failure are also poor prognostic factors.