Primary causes of neutrophilia encompass benign, congenital, and familial syndromes. Another category of primary neutrophilias includes those associated with clonal bone marrow diseases. An 86-year-old woman was seen at the hospital because of fatigue, night sweats, leukocytosis, and splenomegaly. Review of the peripheral-blood smear revealed neutrophilia without dysplastic features, immature forms, or monocytosis. A diagnostic procedure was performed in a new Case Record.
• Is chronic neutrophilic leukemia (CNL) common?
CNL, which was first described approximately a century ago, is rare, with only a few hundred cases reported in the literature. The diagnosis is often made incidentally, but constitutional symptoms such as sweats, fatigue, weight loss, and abdominal symptoms related to splenomegaly, can be present.
• What are the World Health Organization (WHO) diagnostic criteria for CNL?
The diagnosis of CNL, a condition that was first recognized as a distinct entity in the 2001 WHO classification guidelines, requires the presence of unexplained peripheral-blood leukocytosis (≥25×109 white cells per liter), with neutrophils and bands comprising at least 80% of white cells, immature granulocytes comprising less than 10% of white cells, myeloblasts comprising less than 1% of white cells, an absolute monocyte count of less than 1×109 cells per liter, and absence of granulocytic dysplasia; a hypercellular bone marrow with increased granulocytic forms, less than 5% myeloblasts, and normal neutrophil maturation; splenomegaly; exclusion of BCR-ABL1, PDGFRA, PDGFRB, and FGFR1 genetic abnormalities; and exclusion of the diagnoses of polycythemia vera, primary myelofibrosis, and essential thrombocythemia.
Morning Report Questions
Q: What mutations are associated with CNL?
A: In the past several years, it has been shown that up to 90% of patients with CNL harbor a CSF3R (colony-stimulating factor 3 receptor) mutation; the presence of this mutation has been added to the revised 2016 WHO list of diagnostic criteria for CNL. The genetic profile of CNL may include other abnormalities, such as SETBP1, ASXL1, and TET2 mutations. Whether these abnormalities affect the pathogenesis, evolution, or prognosis of CNL is currently not clear. One study suggested that concurrent ASXL1 mutations may be prognostically detrimental.
Q: How is CNL treated, and how does the location of a CSF3R mutation influence the choice of therapy?
A: The most effective therapeutic approach to CNL has not been well defined. Oral agents, including hydroxyurea and busulfan, have been used to control leukocytosis and splenomegaly and improve quality of life. CSF3R mutations occur at two distinct regions: the membrane proximal region and the cytoplasmic tail, which can be truncated by nonsense and missense mutations. Mutations occurring at the former region result in dysregulation of JAK family kinases, whereas mutations occurring at the latter region result in dysregulation of SRC family–TNK2 kinases. Membrane proximal mutations may confer sensitivity to JAK kinase inhibitors such as ruxolitinib, whereas truncation mutations confer sensitivity to the multikinase inhibitor dasatinib but not to JAK kinase inhibitors.