Chronic neutrophilic leukemia
Authors: Ahmad Khoder, Magda Al Obaidi, Anna Babb, Christine Liu, Nicholas C. P. Cross, Barbara J. Bain
Journal: American Journal of Hematology (2018)

An 83-year-old man with a past medical history of chronic kidney disease, hypertension, ischemic heart disease, atrial fibrillation, previous cerebrovascular accident, hypercholesterolemia, and gout was undergoing surveillance after an excised colonic polyp showed adenocarcinoma. He was hospitalized with anemia, sudden worsening of chronic leukocytosis, and deteriorating renal function. At that time he had hematuria, hemoptysis, and epistaxis. There was no splenomegaly on physical examination. Initial investigations showed a normocytic anemia (hemoglobin 70 g/L and mean cell volume 86 fL), white cell count (WBC) 50 × 109/L, platelet count 139 × 109/L, and neutrophil count 45 × 109/L. The neutrophils showed toxic granulation and occasional Döhle bodies (top and bottom left Images). Granulocyte precursors were less than 10% and monocytes were virtually absent. Serum vitamin B12 was greatly elevated (>2000 ng/L) and lactate dehydrogenase was also raised. The patient had no signs of active infection or inflammation and the differential diagnosis was therefore considered to be chronic neutrophilic leukemia or a leukemoid reaction, such as that seen with plasma cell neoplasms (multiple myeloma or monoclonal gammopathy of undetermined significance). A bone marrow aspirate was markedly hypercellular with left shifted granulopoiesis but no increase of blasts cells. Erythropoiesis was greatly reduced. Plasma cells were cytologically normal and not increased in number. Stainable iron was increased but no ring sideroblasts were seen. There was a mild balanced increase in serum-free light chains and no paraprotein was detected. Computed tomography scanning of chest and abdomen disclosed no splenomegaly, lymphadenopathy, bone lesions, or signs of a neoplastic condition. The suspected diagnosis of chronic neutrophilic leukemia (CNL) was confirmed by subsequent analyses. Cytogenetic analysis was normal and fluorescence in situ hybridization (FISH) excluded BCR-ABL1, FIP1L1-PDGFRA, and rearrangement of PDGFRB and FGFR1. Sequencing of a panel of 33 genes, known to be pathogenic in myeloid neoplasms, detected a T618I mutation in CSF3R exon 14.1 No mutations in SETBP1 or ASXL1 were detected. The patient was keen to have a trial of treatment but was not responsive to a renally adjusted dose of hydroxycarbamide or subsequent cyclophosphamide or idarubicin plus etoposide. The WBC peaked at 198 × 109/L with death occurring within 2 months from presentation. The molecular abnormality most strongly associated with CNL is CSF3R mutation with a minority of patients having a JAK2 V617F mutation. Interestingly, the blood film is not particularly useful in distinguishing CSF3R-mutated CNL from a leukemoid reaction since toxic granulation and Döhle bodies are common in both,2 in one instance resulting from the action of granulocyte colony-stimulating factor (G-CSF) and in the other from a mutation in the gene encoding the G-CSF receptor. Investigation to exclude a plasma cell or other neoplasm and molecular analysis to confirm CNL are therefore essential. The minority of cases with a JAK2 V617F mutation less often have “toxic” changes in neutrophils, this being reported in only 2 of 8 published cases, when the publication permitted this to be assessed.2 No author has a conflict of interest.