Chronic neutrophilic leukemia: new science and new diagnostic criteria

Abstract

Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes.

Septic Shock Predisposed by an Underlying Chronic Neutrophilic Leukemia with an Atypical Presentation; A Case Report

“…Interestingly, his CNL was labeled atypical due to the following: First, our patient's cytogenetics did not yield a CSF3R line mutation which is a diagnostic components of the revised WHO CNL diagnostic criteria [1, 13] (Table 1). The CSF3R line mutation has been identified as a strong molecular marker for CNL and studies showed up to 90% of CNL patients were carriers versus 40% in those who were diagnosed with aCML [10].…”

“…A variant in the JAK2 gene is typically under the umbrella of BCR-ABL negative MPNs such as polycythemia vera (PV) and essential thrombocythemia (ET). According to the WHO, the presence of a JAK2 variant is considered as part of PV's and ET's major criteria [1, 13] and its absence is considered a key criteria for CNL and aCML [1, 13]. However, based on our patient's blood work, polycythemia vera and essential thrombocythemia as diagnosis were very less likely due to how our patient did not have an abnormally elevated hemoglobin and hematocrit or even a platelet count in the category of true thrombocythemia, respectively [1, 13].…”

“…Due to the over-all presentation of the patient's blood work which was suggestive of a myeloproliferative disorder (before and after septic episode) , along with a bone marrow aspirate and biopsy analysis as detailed above ( before and after septic episode [when the patient was clinical stabilized on an extended course of antibiotics]), the patient was diagnosed with CNL which presented atypically, due to the absence of a mutation in the CSF3R protein line and the presence of a rearrangement in the JAK2 gene [1, 13] (Table 1).…”

“…Chronic neutrophilic leukemia (CNL) is an extremely rare MPN with an unknown true incidence to date [9]. About 200 cases have been reported, with a possible lower true incidence if the present World Health Organization (WHO) diagnostic criteria are taken into consideration [1, 6, 13]. CNL is characterized by the recently revised WHO criteria with its main points being the following: First, the presence of a proliferation of mature neutrophils with leukocytosis of > 25×10 9 /L (> 80% segmented neutrophils plus bands), < 10% immature granulocytes and rarely observed blasts with no identified dysgranulopoiesis in the peripheral blood.…”

“…Fourth, there are no identified rearrangements of PDGFRA, PDGFRB or FGFR1 or PCM1-JAK2 protein lines. Finally, the presence of a mutation in the CSF3R line is observed, or if absent, the presence of sustained neutrophilia (at least 3 months), splenomegaly and no other identifiable cause of reactive neutrophilia including the absence of a plasma cell neoplasm, or, if present, the demonstration of myeloid cell clonality by cytogenetics [1, 13] (Table 1). The identification of the presence of the CSF3R line mutation which has been highly linked to CNL, based on landmark studies, served as a first strong biomolecular marker that allowed for the elucidation of CNL from other BCR-ABL negative MPNs resulting to the updated WHO criteria from its 2008 counterpart [4, 6, 12].…”