Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management

Abstract

Disease Overview: Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly.The 2013 seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting.Diagnosis: In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 Â 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.Management: There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality.Disease Updates: Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance.Although accurate prognostic stratification and therapeutic decision-making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.

Case report: Chronic neutrophilic leukemia associated with monoclonal gammopathies. A case series and review of genetic characteristics and practical management

“…Mutated ASXL1 as in patient 3, resulting in disrupted epigenetic regulation, is associated with a negative prognosis in CNL. Mutational frequency is varying from 30% to 81% (1,22). Mutated TP53 is characterized as a negative prognostic factor in myeloid and lymphoid malignancies (24, 25).…”

“…Chronic neutrophilic leukemia (CNL) is an infrequent BCR::ABL1 negative myeloproliferative neoplasm (MPN) defined by sustained, mature neutrophilia and bone marrow hypercellularity with granulocytic hyperplasia ( 1 , 2 ). Approximately 200 CNL cases have been described; however, many of these do not meet the current diagnostic criteria ( 3 ).…”

“…Approximately 32% of CNL cases are associated with plasma cell dyscrasias, wherein CSF3R tends to be less frequently mutated ( 1 , 7 ). It remains unclear whether both entities should be considered clonally related or neutrophilia is provoked by the plasma cell dyscrasia ( 1 ). The majority of CNL-associated paraproteinemias express lambda light chains ( 8 ).…”

CSF3R T618I mutated chronic myelomonocytic leukemia: A proliferative subtype with a distinct mutational profile

“…Similarly, CSF3R T618I mutated CNL seems to have a mutational profile different from CSF3R non-T618I mutated CNL regarding the SETBP1 mutation; this mutation is more frequent in CSF3R T618I mutated CNL (∼50%) than in CSF3R non-T618I mutated CNL (∼5–10%). The mutational frequency of ASXL1 is similar between these two subtypes of CNL [ 4 , 5 , [19] , [20] , [21] ].…”

“…Finally, the proposed mechanism of CSF3R T618I pathogenesis may provide a rationale for molecularly-directed targeting of CSF3R T618I mutated CMML with JAK2 kinase inhibitors such as ruxolitinib [ 6 , 21 ]. Encouragingly, the clinical benefit of ruxolitinib was recently demonstrated in a subset of CNL patients (with lower-risk features) harboring CSF3R T618I mutation with hematologic responses and allele burden reduction [22] .…”