[Chronic neutrophilic leukemia/chronic eosinophilic leukemia].

Chronic neutrophilic leukemia (CNL) is a clonal disorder that is characterized by increasing mature neutrophils. Colony stimulating factor 3 receptor (CSF3R) T618I mutation was frequently identified in patients with CNL and is defined as a molecular marker of the disease. Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study. In particular, ruxolitinib was more efficient for patients with CSF3R mutation. Allogeneic stem cell transplantation (Allo-SCT) may be a curative treatment for CNL. On the other hand, further studies are needed to define the optimal method of transplantation, source of donor, conditioning therapy, and timing of transplantation. Chronic eosinophilic leukemia (CEL) is a clonal disorder that is characterized by increasing eosinophils. In the World Health Organization Classification 5th edition, diagnostic criteria for CEL are renewed. Because the new criteria will be more specific for CEL than criteria in the older edition, "not otherwise specified (NOS) " is removed from the name of the disease. Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.

Chronic neutrophilic leukemia preceded by myelodysplastic syndromes.

Chronic neutrophilic leukemia (CNL) is primarily diagnosed by excluding myelodysplastic syndromes (MDS). We report the case of a patient who developed secondary CNL 3 years after hypoplastic MDS. We used droplet digital polymerase chain reaction mutation detection assay to analyze genomic alterations during the progression from MDS to CNL. At the time of MDS diagnosis, U2AF1 Q157P and SETBP1 D868N were dominant and additional mutation of ASXL1 1934_insG was observed. CSF3R T618I and SETBP1 D868N were increasing at the time of CNL diagnosis. We revealed the accumulation of multiple gene mutations during CNL development from MDS. This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia.

Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation.

Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review.

BACKGROUND: Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL-PCD) and lymphocytic proliferative disease (CNL-LPD). METHODS: The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL-MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL-PCD and CNL-LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. RESULTS: A 73-year-old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG-λ monoclonal M protein. A CT scan showed splenomegaly. Next-generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL-MGUS. We summarized 10 cases of CNL-PCD and 1 case of CNL-LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL-PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL-PCD. CONCLUSIONS: Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL-PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL-PCD.

Case and review: Cutaneous involvement by chronic neutrophilic leukemia vs Sweet syndrome- A diagnostic dilemma.

Chronic neutrophilic leukemia (CNL) is a rare leukemia with approximately 150 total cases reported. Cutaneous neutrophilic infiltrates, including Sweet syndrome (SS) and leukemia cutis (LC), have been reported in six patients with CNL. In the setting of CNL, these two conditions are difficult to differentiate due to clinical and histopathological similarities, but it is important to do so because LC is associated with a worse prognosis. In general, SS is distinguished by its tenderness, fever, and improvement with steroids (vs chemotherapy for LC). Biopsy of LC reveals immature leukocytes, whereas SS shows almost exclusively mature leukocytes, but morphology alone may not be sufficient in some cases. Here, we report a case of a 72-year-old male with CNL and a cutaneous eruption with clinical and pathological features which made the distinction between the two diseases difficult.

[Fatal intracerebral hemorrhage in a patient with chronic neutrophilic leukemia: About one case and literature review]. / Hémorragie intracérébrale fatale chez un patient atteint d'une leucémie chronique à polynucléaires neutrophiles : à propos d'un cas et revue de la littérature.

INTRODUCTION: Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative syndrome characterized by a significant increase in mature neutrophils. One of the most serious complications is the occurrence of bleeding events, which may sometimes lead to death. CASE REPORT: A 75-year-old patient presented with CNL, complicated by a severe bleeding phenotype. Biological investigations revealed platelet function defect and increase in neutrophil elastase. The follow-up was marked by an intracranial hemorrhage leading to the patient's death 7 months after diagnosis. CONCLUSION: This bleeding phenotype has been reported several times in patients with CNL. However, the pathophysiological mechanisms that cause bleeding are not yet fully understood.

Chronic neutrophilic leukemia presenting as secondary gout: Report of a rare myeloproliferative disorder.

Chronic neutrophilic leukemia is a rare leukemia seen in middle aged and elderly people, characterized by neutrophilic leukocytosis with no significant increase in granulocytic precursors. The chief criteria for diagnosis include total leukocyte count ≥25 × 109/L, >80% of white blood cells being mature neutrophils (segmented and band forms), immature granulocytic precursors ≥10% in the peripheral blood, and hypercellular marrow. In addition to this, there must be no evidence of dysplasia, monocytosis or BCR-ABL1, PDGFR-A, PDGFR-B, or FGRF-1 rearrangements. Moreover, the cause of neutrophilia should not be attributed to any other myeloproliferative disorders or to physiologic neutrophilia.We present two patients with this rare disorder who presented with gout as the initial symptom.

Analysis of gene mutation characteristics in patients with chronic neutrophilic leukaemia.

Objective: This study aims to investigate the gene mutation characteristics of chronic neutrophilic leukaemia (CNL). Method: This study retrospectively analyses the molecular biological characteristics, laboratory characteristics and clinical data of four patients with CNL that were admitted in the second Hospital of Shanxi Medical University from May 2014 to October 2016. On the basis of the molecular biological data of 22 patients with CNL and 4 patients with CNL, we further analysed the characteristics of CNL molecular mutation. Results: Two out of the four patients with CNL were carriers of colony-stimulating factor 3 receptor (CSF3R) mutation, among which two were carriers of CSF3R T618I mutation combined with ASXL1 mutation and SETBP1 mutation, and two were only carriers of JAK2 V617F mutation. According to the molecular biological data of 22 patients with CNL, 20 patients were positive for CSF3R mutation. Two patients were positive for JAK2 V617F mutation. A total of 10 patients were positive for SETBP1 mutation which was correlated with the CSF3R T618I gene mutation (P = 0.03). A total of 13 patients were positive for ASXL1 mutation. No patients carried mutations in ASXL2 and MPL genes. Conclusion and Discussion: CSF3R mutation is the main tumorigenic mutation in CNL, in which CSF3R T618I mutation is the main mutation, and an extremely small number of CNL patients may be caused by JAK2 V617F mutation. SETBP1 and ASXL1 are the most common concomitant mutations in CNL with CSF3R mutation, and SETBP1 and CSF3R T618Imutations may have a certain correlation.

Chronic neutrophilic leukemia, an extremely rare cause of neutrophilia in childhood: Cure with hematopoietic stem cell transplantation.

CNL is a rare myeloproliferative disorder frequently seen in older adults. A significant proportion of patients show progression to AML. Here, we report the case of a patient with FA who was monitored for leukopenia but who developed leukocytosis during the follow-up and was diagnosed with CNL probably after an acquired CSF3R mutation. Because the patient had FA, which could accelerate the progression to AML, an HSCT was performed, which resulted in cure. This patient (aged 12 years) is one of the youngest patients reported to develop CNL as well as the first FA patient with a diagnosis of CNL.

Coexisting of bone marrow fibrosis, dysplasia and an X chromosomal abnormality in chronic neutrophilic leukemia with CSF3R mutation: a case report and literature review.

BACKGROUND: Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) with less than 40 cases of patients being reported or clinically suspected meeting with 2008 World Health Organization ("WHO") diagnostic criteria. The current diagnosis of CNL remains to exclude other diseases. Recently, a new biomarker of CSF3R mutations that is almost invariably present in CNL has been identified. There is no effective treatment for CNL, therefore prognosis of the disease is poor, but it may be attributed to the presence of both SETBP1 and CSF3R gene mutations. The presence or absence of CSF3R mutation did not affect survival, whereas a trend for shortened survival was observed among patients with SETBP1-mutation. CASE PRESENTATION: Here we report a 65-year old woman patient who presented with leukocytosis without sign of fever and tumors. Bone marrow aspirates showed a markedly hypercellular feature with 76%-92% myeloid and the dysplastic changes were found in about 7% of neutrophils cells. The bone marrow biopsy demonstrated marrow fibrosis with Gomori staining positive (+++~++++). Cytogenetic analysis showed 46,X,del (X) (q22). No molecular markers of BCR/ABL1 rearrangement (P210, P230, P190 and variably), JAK2V617F, FIP1L1-PDGFRA, TEL-PDGFRB, ZNF198-FGFR1 and SETBP1 mutations were identified, however, the CSF3R gene membrane proximal mutation (c.1853C > T/p.T618I sites) was detected by PCR techniques. The patient was diagnosed with CNL and died in about 2 months after disease diagnosis. CONCLUSION: In clinical course, the CNL concurrently with severe bone marrow fibrosis and dysplastic features as well as X chromosomal abnormality may predict a worsening prognosis regardless of SETBP1 mutation status.

[Chronic neutrophilic leukemia complicated with multiple myeloma: two cases report and literature review].

OBJECTIVE: To explored the diagnosis and treatment of chronic neutrophilic leukemia (CNL) complicated with multiple myeloma (MM). METHODS: The clinical features and molecular biological characteristics of 2 patients with CNL complicated with MM were summarized, and the diagnosis and treatment of the patients were retrospectively reviewed. RESULTS: The diagnosis of CNL complicated with MM was established in 2 cases. Case 1 had CSF3R mutation (P733T), but CSF3R-exon 14 mutation and SETBP1 mutation were all negative. The neutrophil count returned to normal when MM was successfully treated in case 1. When the patient relapsed, neutrophil count increased again. CONCLUSION: Coexistence of CNL and MM is rare. CSF3R is a very important molecular marker for CNL. To the best of our knowledge, it's the first time to report the coexistence of CNL and MM carried CSF3R mutation (P733T). Chemotherapy regimens for MM may be effective in the treatment of CNL complicated with MM.

A CSF3R T618I Mutation in a Patient with Chronic Neutrophilic Leukemia and Severe Bleeding Complications.

Chronic neutrophilic leukemia (CNL) is a rare form of myeloproliferative neoplasm characterized by the drastic elevation of mature neutrophils. One of the major causes of death among patients with CNL is severe bleeding; however, the difficulty of accurately diagnosing this disease has caused confusion in this field. Recently, somatic mutations of the CSF3R gene have been associated with CNL. This has led to the establishment of more accurate diagnostic criteria for CNL. We herein report a case study of a patient with CNL with a T618I point mutation on the CSF3R gene who showed severe bleeding.