The spectrum of Ph-negative disease: CNL and CSF3R-related disorders

Chronic neutrophilic leukemia (CNL) is a very rare myeloid neoplasm characterized by peripheral blood neutrophilia and a hypercellular marrow with increased granulopoiesis. An activating mutation in CSF3R is present in 80% to 90% of cases. CNL displays some biological overlap in terms of clinical presentation and behavior, as well as genetic profile, with several other myeloid neoplasms, particularly myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and other MPN. Distinguishing these related entities can be challenging, requires close attention to peripheral blood and bone marrow morphology, and can be informed by the mutation pattern: CNL is strongly associated with CSF3R mutation, usually lacks JAK2, MPL, or CALR mutations, and, by definition, lacks BCR::ABL1 rearrangement. Pitfalls in diagnosis include subjectivity in assessing neutrophil dysplasia and distinguishing true neoplastic neutrophilia from reactive neutrophilias that may be superimposed upon or occur as a manifestation of the progression of other myeloid neoplasms. Accurate distinction between neutrophilic myeloid neoplasms is important, as it helps guide patient management and may disclose specific genetic lesions amenable to targeted therapy.