Chronic Neutrophilic Leukemia Research Articles

ASSOCIATION OF JAK2 F617 ALLELE BURDEN WITH HEMATOLOGICAL PARAMETERS IN MPD PATIENTS

Objective: A point mutation in the JAK2 gene, resulting in the substitution of valine for phenylalanine (JAK2 V617F), has been associated with myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, myelodysplastic syndromes, chronic myelomonocytic leukemia, systemic mastocytosis, chronic neutrophilic leukemia, and eosinophilic disorders. Material and Methods: The relation of JAK2 V617F mutation has been studied in myeloproliferative disorder patients by qPCR. The F617 allele was calculated using a standard calibration curve, including less and more than 50% mutational load groups. Results: A significant relation was found among wild type (wt), less and more than 50% groups, Regarding erythrocyte, hematocrit, platelet, and leukocyte levels. A statistically significant relation was found between wt and more than 50% of groups regarding hemoglobin levels. The mutational load increase has been shown to induce erythrocyte, hematocrit, and leukocyte levels, except platelet levels. Conclusion: In patients with myeloproliferative disorders, qPCR screening of JAK2 gene mutation is indicated.

Transcriptomic signature can distinguish chronic neutrophilic leukemia from ambiguous neutrophilic leukemias.

Identifying uncommon neutrophilic leukemias presents a challenging task, owing to the analogous morphological characteristics and the dearth of molecular markers. The transcriptomic profile of bone marrow cells in this disease subset has been rarely explored. The OHSU-CNL dataset, encompassing clinical parameters and parallel transcriptomic matrix, was downloaded from the Genomic Data Commons (GDC) database. Distinctive co-expressed gene modules and pivotal genes for chronic neutrophilic leukemia (CNL) were identified using R software. Subsequently, a diagnostic model for CNL denoted as CNL-5 was formulated employing least absolute shrinkage and selection operator (LASSO) regression analysis. The diagnostic power of the CNL-5 model was compared with conventional clinical/genetic markers via multi-ROC analysis. The divergence in overall survival between CNL-5 risk groups was delineated by Kaplan-Meier analysis, and the predictive power (AUC and Harrison's C index) was determined by time-dependent ROC. Cell signaling pathways associated with CNL-5 risk were identified by genomic set enrichment analysis (GSEA). Neither clinical indicators nor genetic markers were sufficient to classify neutrophilic leukemias. Through weighted gene co-expression network analysis (WGCNA), the brown module was discerned to be CNL-specific (p = 8e-16, R2 = 0.5). Using LASSO analysis, the CNL-5 model, with risk scores based on the weighted expression value of five genes (PDCD7/CR2/ZSCAN20/TRIM68/LILRA6) dichotomized patients into CNL-like and Atypical-CNL groups. Compared to the Atypical-CNL group, the CNL-like group demonstrated a clinical phenotype more consistent with CNL and had a significantly higher prevalence of CSF3R mutations (p<0.05). Additionally, the AUC of the CNL-5 risk model surpassed that of conventional clinical/genetic markers, as validated by the GSE42731 dataset. Poorer survival was revealed in the high-risk group than in the low-risk group defined by the CNL-5 model. GSEA identified CNL-5-associated pathways, such as the inhibition of oxidative phosphorylation and the activation of IL6-JAK-STAT3 signaling. A novel expression signature-based diagnostic assessment for CNL was developed, which showed better diagnostic utility than conventional indicators.

Dual ASXL1 and CSF3R mutations drive myeloid-biased stem cell expansion and enhance neutrophil differentiation.

Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). CNL is a myeloproliferative neoplasm (MPN) driven by activating mutations in the Colony Stimulating Factor 3 Receptor (CSF3R), which cause excessive neutrophil production. Despite the high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human MPNs. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem cells, which is tempered by adding Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased long-term hematopoietic stem cells. As the mice age, they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation, activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations have increased H3K4me1 at neutrophil-associated enhancers. Mutant ASXL1 is known to decrease the genome-wide abundance of the repressive histone mark H2AK119ub. Although we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1 and CSF3R dual-mutant MPN.

Role of allo-HCT in "nonclassical" MPNs and MDS/MPNs: recommendations from the PH&G Committee and the CMWP of the EBMT.

Role of allo-HCT in "nonclassical" MPNs and MDS/MPNs: recommendations from the PH&G Committee and the CMWP of the EBMT.

Chronic Neutrophilic Leukemia: Advances in Diagnosis, Genetic Insights, and Management Strategies.

CNL is a rare subtype of MPNs characterized by persistent neutrophilia, bone marrow hypercellularity, and specific genetic mutations, particularly in the CSF3R gene. Advances in molecular diagnostics have greatly enhanced our understanding of CNL, distinguishing it from other myeloproliferative disorders and refining diagnostic criteria. This review provides an updated overview of CNL, focusing on breakthroughs in genetic profiling, including novel mutations with potential prognostic value and implications for targeted therapy. We discuss current management strategies, emphasizing the role of JAK inhibitors, allogeneic stem cell transplantation, and evolving investigational treatments. Challenges in early diagnosis, therapeutic resistance, and future directions in research are also addressed, underscoring the need for a personalized medicine approach to improve outcomes for patients with CNL.

Distribution of different classes of CSF3R mutations and co-mutational pattern in 360 myeloid neoplasia

The colony-stimulating factor 3 receptor (CSF3R) plays an essential role in differentiation, growth, and survival of granulocytes. Driver mutations in CSF3R gene represent a diagnostic marker of chronic neutrophilic leukemia (CNL). Less commonly, these mutations are observed in other myeloid neoplasms but their pathogenetic and prognostic role is still unclear. Here, we analyzed a large cohort of myeloid neoplasms to evaluate the incidence of CSF3R mutations and co-mutational profile. Mutational analysis was performed using targeted NGS myeloid panel in a consecutive cohort of 360 patients with myeloid neoplasms. Mutations in CSF3R were identified in 20/360 (5.6%) cases. A CSF3R gene mutation was present in 13/179 AML cases (7.3%), in 2/27 (7.4%) CMML cases, in 1/94 (1.1%) MDS cases and in 4/60 (6.7%) other myeloid neoplasms. The frequencies of patients with CSF3R mutations lowered to 2.8% in all cases and 3.4% in AML, excluding cases with variants of uncertain significance (VUS). A total of 23 mutations of CSF3R gene were detected, half localized in the extracellular domain, 5 in the transmembrane region (type I) and 6 mutations in the cytoplasmic domain (type II). In AML, CSF3R mutations were more frequent in patients harboring CBF alterations (25.0%) and CEBPA mutations (11.8%). Two cases with AML harboring pathogenic CSF3R variants were primary refractory to induction therapy. CMML cases with T618I variant showed a myeloproliferative phenotype. Overall, our findings support the notion that CSF3R variants, particularly type I and II pathogenic mutations, may modulate the phenotypic features of leukemic cells in myeloid neoplasia.

CSF3R Gln776X and ASXL1 mutations in multiple myeloma associated with chronic neutrophilic leukemia: case report and literature review.

CSF3R Gln776X and ASXL1 mutations in multiple myeloma associated with chronic neutrophilic leukemia: case report and literature review.

Ruxolitinib and pegylated interferon in Chronic Neutrophilic Leukemia due to a pathogenic CSF3R germline variant: a case report

Ruxolitinib and pegylated interferon in Chronic Neutrophilic Leukemia due to a pathogenic CSF3R germline variant: a case report

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.

Abstract 4140731: Trends, Outcomes and Predictors of Mortality in Patients with Myeloproliferative Neoplasms Undergoing Percutaneous Coronary Intervention: Insights from National Database

Introduction: Myeloproliferative neoplasms (MPN) are stem cell disorders that include include polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML), primary myelofibrosis (PMF), chronic neutrophilic leukemia, and less well defined entities such as chronic eosinophilic leukemia. MPN are associated with an increased cardiovascular risk including acute coronary syndrome. However, there is a lack of comprehensive data regarding the rate of coronary revascularization, as well as the in-hospital characteristics and outcomes for MPN patients. Objective: We aimed to evaluate the temporal trends and outcomes of percutaneous coronary intervention (PCI) among patients with MPN. Methods: The National Inpatient Sample database from 2016 to 2020 was queried to identify all PCI hospitalizations. Temporal trends and outcomes of patients with and without MPN following PCI were described. Propensity score matching (PSM) was implemented to compare outcomes between MPN and non-MPN groups. Results: Our study included 2,237,210 PCI hospitalizations with 7,560 (0.27%) patients having MPN. Throughout the study period, the prevalence of MPN among PCI admissions remained stable (p-value for trend = 0.12). Within the MPN subgroup, ET was the predominant condition (53.2%), followed by PV (24.2%), CML (19.6%) and PMF (3.0%), with no significant temporal variation in the distribution of these subtypes. Patients with MPN had higher prevalence of cardiovascular comorbidities than non-MPN patients. Following propensity score matching, MPNs were significantly associated with an higher risk of blood transfusions (OR: 1.66, 95% CI: 1.22-2.24, p=0.001) and AKI (OR: 1.39, 95% CI: 1.17-1.65, p&lt;0.001). In contrast, the risk of in-hospital mortality (OR: 1.18, 95% CI: 0.83-1.69, p=0.354 and bleeding (OR: 1.43, 95% CI: 0.90-2.27, p=0.127) did not significantly differ between the two groups. Conclusion: Our study demonstrated that while the prevalence of MPN among patients undergoing PCI remained stable, those with MPN faced higher risks of bleeding, blood transfusion and acute kidney injury. Further research is warranted to explore the underlying reasons for these increased risks and to improve outcomes in this high risk group.

CSF3RT618I Is Stabilized By Calnexin and Induces Unfolded Protein Response (UPR) and ER-Phagy: A Pro-Survival Pathway for Oncogenic Misfolded CSF3R Proteins in Chronic Neutrophilic Leukemia (CNL)

CSF3RT618I Is Stabilized By Calnexin and Induces Unfolded Protein Response (UPR) and ER-Phagy: A Pro-Survival Pathway for Oncogenic Misfolded CSF3R Proteins in Chronic Neutrophilic Leukemia (CNL)

Neoplasias mieloproliferativas crónicas Filadelfia negativas

Neoplasias mieloproliferativas crónicas Filadelfia negativas

Neoplasias mieloproliferativas crónicas. Clasificación. Leucemia mieloide crónica

Neoplasias mieloproliferativas crónicas. Clasificación. Leucemia mieloide crónica

Chronic Neutrophilic Leukemia Developing in a Patient with Myelodysplastic Syndrome: A Case Report and Review of the Literature

Chronic Neutrophilic Leukemia Developing in a Patient with Myelodysplastic Syndrome: A Case Report and Review of the Literature

Distinct clinical profiles and patient outcomes in aCML and CNL.

The classification of atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) as a single disease entity remains a topic of debate. To elucidate the characteristics of both entities, this retrospective cohort study was conducted, encompassing 36 cases of aCML and 18 cases of CNL. We discovered that aCML and CNL presented distinct blood counts, genetics, molecular profiles and outcomes. Specifically, hemoglobin levels (P < 0.001) and platelet counts (P < 0.001) were significantly lower in aCML cases than in CNL cases, with no significant difference in mean white blood cells (P = 0.637). The proportion of abnormal karyotypes was higher in aCML cases compared with CNL cases (P = 0.010). Notably, we found that aCML and CNL showed distinct gene expression profiles by transcriptome sequencing technology. The median follow-up duration for the entire cohort was 8months (rang 0.4 to 36.6months), and the median overall survival (OS) was significantly shorter in aCML cases (7.3months, 95%CI 5.4 to 20.5months) than in CNL cases (median OS not reached). The one-year OS rate for aCML patients was 31.0% (9/29), compared to 92.9% (13/14) for CNL patients. In conclusion, our study supports the notion that aCML and CNL are indeed distinct disease entities characterized by unique hematological features and clinical outcomes.

Chronic Neutrophilic Leukemia in A 32-Year-Old Female. A Rare Discovery, Diagnostic Dilemma and review of the current literature.

Chronic neutrophilic leukemia (CNL) is a rare disease, with an annual incidence of about 1 new case per million people, a little male preponderance and a median diagnostic age of approximately 65. The disease's clinical manifestations can range from asymptomatic to extremely symptomatic, with severe splenomegaly and constitutional symptoms. Most of CNL patients succumb from disease-related complications or progress to acute myeloid leukemia, which leaves their prognosis poor. A 32-year-old female experienced heartbeat awareness for 4 months, worsening over time, with fever, headache, dizziness, joint stiffness, pain, reduced joint movement, and body weakness. After initial evaluation and investigations, a diagnosis of CNL was reached with differential diagnoses of reactive neutrophilia/leukemoid reaction, chronic myeloid leukemia (CML), neutrophilic-CML (CML-N). Clinicians should have a high index of suspicion to diagnose and differentiate them. Immediate treatment was initiated to stabilize the patient before further diagnostic workups but disease rapid progression and the impact limited diagnostic investigations on patient outcomes. Therefore, a streamlined approach to managing CNL is crucial in time-sensitive situations, as it ensures prompt accurate diagnosis and intervention.

Hereditary chronic neutrophilic leukemia in a four-generation family without transformation to acute leukemia.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by peripheral blood neutrophilia, marrow granulocyte hyperplasia, hepatosplenomegaly, and driver mutations in the colony-stimulating factor 3 receptor (CSF3R). Designation of activating CSF3R mutations as a defining genomic abnormality for CNL has led to increased recognition of the disease. However, the natural history of CNL remains poorly understood with most patients reported being of older age, lacking germline data, and having poor survival, in part due to transformation to acute leukemia. CSF3R driver mutations in most patients with CNL have been reported to be acquired, although rare cases of germline mutations have been described. Here, we report the largest pedigree to date with familial CNL, spanning four generations with affected family members ranging in age from 4 to 53 years, none of whom have transformed to acute leukemia. A heterozygous T618I CSF3R mutation was identified in peripheral blood and mesenchymal stromal cells from the proband and in all affected living family members, while the unaffected family members tested were homozygous wild type. We show that the T618I mutation also confers a survival advantage to neutrophils in an MCL1-dependent manner. Collectively, these data provide additional insights into the natural history of familial CNL arising from T618I CSF3R mutations and suggest that enhanced neutrophil survival also contributes to the high neutrophil count observed in patients with CNL.

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia

Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management.

Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic "[MDS]/MPN with neutrophilia" per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 109/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of an activating CSF3R mutation. ICC criteria are harmonized with those of other myeloid entities, with a key distinction being lower leukocytosis threshold (≥13 × 109/L) for cases CSF3R-mutated. Criteria for aCML include leukocytosis ≥13 × 109/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia for MDS-thresholds (ICC). In both classifications ASXL1 and SETBP1 (ICC), or SETBP1 ± ETNK1 (WHO) mutations can be used to support the diagnosis. Both diseases show hypercellular bone marrow due to a granulocytic proliferation, aCML distinguished by dysplasia in granulocytes ± other lineages. Absence of monocytosis, rare/no basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions, are mandated. Cytogenetic abnormalities are identified in ~1/3 of CNL and ~15-40% of aCML patients. The molecular signature of CNL is a driver mutation in colony-stimulating factor 3 receptor-classically T618I, documented in >80% of cases. Atypical CML harbors a complex genomic backdrop with high rates of recurrent somatic mutations in ASXL1, SETBP1, TET2, SRSF2, EZH2, and less frequently in ETNK1. Leukemic transformation rates are ~10-25% and 30-40% for CNL and aCML, respectively. Overall survival is poor: 15-31 months in CNL and 12-20 months in aCML. The Mayo Clinic CNL risk model for survival stratifies patients according to platelets <160 × 109/L (2 points), leukocytes >60 × 109/L (1 point), and ASXL1 mutation (1 point); distinguishing low- (0-1 points) versus high-risk (2-4 points) categories. The Mayo Clinic aCML risk model attributes 1 point each for: age >67 years, hemoglobin <10 g/dL, and TET2 mutation, delineating low- (0-1 risk factor) and high-risk (≥2 risk factors) subgroups. Management is risk-driven and symptom-directed, with no current standard of care. Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Hematopoietic stem cell transplant is the only potentially curative modality and should be considered in eligible patients. Recent genetic profiling has disclosed CBL, CEBPA, EZH2, NRAS, TET2, and U2AF1 to represent high-risk mutations in both entities. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.

Analysis of CSF3R mutations in atypical chronic myeloid leukemia and other myeloid malignancies

Analysis of CSF3R mutations in atypical chronic myeloid leukemia and other myeloid malignancies