Abstract：
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.
摘要：
慢性中性粒细胞白血病（CNL）是一种罕见的BCR：：ABL1阴性骨髓增殖性肿瘤（MPN），由持续的成熟中性粒细胞增多症和骨髓粒细胞增生定义。非典型慢性粒细胞白血病（aCML）（根据世界卫生组织[WHO]，骨髓增生异常与中性粒细胞增多症）是一种MDS/MPN重叠疾病，其特征是增生性中性粒细胞增多症和循环髓系前体。两者均表现为频繁的肝脾肿大，较不常见，出血,白血病转化和死亡率高。2022年修订的WHO分类保留了白细胞增多≥25×109/L的CNL诊断标准，中性粒细胞≥80%，循环前体<10%，没有发育不良，和激活CSF3R突变的存在。ICC标准与其他骨髓实体的标准相协调，一个关键的区别是CSF3R突变病例的白细胞增多阈值较低（≥13×109/L）。aCML的标准包括白细胞增多≥13×109/L，恶性粒细胞生成,循环髓样前体≥10%，和至少一个MDS阈值（ICC）的血细胞减少症。在ASXL1和SETBP1(ICC)这两个分类中，或SETBP1±ETNK1（WHO）突变可用于支持诊断。两种疾病均显示由于粒细胞增殖而导致的高细胞骨髓，ACML通过粒细胞±其他谱系中的发育不良来区分。缺乏单核细胞增多症，罕见/无嗜碱性粒细胞,或者嗜酸性粒细胞增多,<20%爆炸,排除其他MPN，MDS/MPN,和酪氨酸激酶融合，是授权的。在约1/3的CNL和约15-40%的aCML患者中鉴定出细胞遗传学异常。CNL的分子特征是集落刺激因子3受体的驱动突变-经典的T618I，记录在>80%的病例中。非典型CML具有复杂的基因组背景，在ASXL1，SETBP1，TET2，SRSF2，EZH2中复发性体细胞突变的发生率很高，而在ETNK1中的发生率较低。CNL和aCML的白血病转化率约为10-25%和30-40%，分别。总体生存期较差：CNL为15-31个月，aCML为12-20个月。MayoClinicCNL生存风险模型根据血小板<160×109/L（2分）对患者进行分层，白细胞>60×109/L(1分),和ASXL1突变（1分）；区分低（0-1分）和高风险（2-4分）类别。梅奥诊所aCML风险模型每个属性为1分：年龄>67岁，血红蛋白<10g/dL，和TET2突变，划分低(0-1个危险因素)和高(≥2个危险因素)亚组.管理是风险驱动和症状导向的，没有当前的护理标准。最常用的药物包括羟基脲，干扰素，Janus激酶抑制剂，和低甲基化剂，虽然没有一个是改变疾病的。造血干细胞移植是唯一可能治愈的方式，应在符合条件的患者中考虑。最近的遗传分析已经披露了CBL，CEBPA,EZH2NRAS,TET2和U2AF1代表两个实体中的高风险突变。可操作的突变（NRAS/KRAS，ETNK1)也已被确定，支持新型药物靶向涉及的途径。评估新药的临床前和临床研究(例如，费地替尼,阶段2)和组合进行了详细说明。
