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.

中文翻译：

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慢性中性粒细胞白血病和非典型慢性粒细胞白血病：2024 年诊断、遗传学、风险分层和管理更新


慢性中性粒细胞白血病 (CNL) 是一种罕见的 BCR::ABL1 阴性骨髓增生性肿瘤 (MPN)，其定义为持续性成熟中性粒细胞增多和骨髓粒细胞增生。非典型慢性粒细胞白血病 (aCML)（根据世界卫生组织 [WHO] 的定义，骨髓增生异常“[MDS]/MPN 伴中性粒细胞增多”）是一种 MDS/MPN 重叠性疾病，其特征为发育不良中性粒细胞和循环骨髓前体细胞。两者均表现为频繁的肝脾肿大，较少见的是出血，且白血病转化率和死亡率很高。 2022 年修订的 WHO 分类保留了 CNL 诊断标准，即白细胞增多 ≥25 × 10 ⁹ /L、中性粒细胞 ≥80%、循环前体细胞 <10%、不存在不典型增生以及存在激活的 CSF3R 突变。 ICC 标准与其他骨髓实体的标准一致，主要区别是 CSF3R 突变病例的白细胞增多阈值较低 (≥13 × 10 ⁹ /L)。 aCML 的标准包括白细胞增多 ≥13 × 10 ⁹ /L、粒细胞生成障碍、循环骨髓前体细胞≥10%，以及至少一种 MDS 阈值 (ICC) 血细胞减少症。在这两个分类中，ASXL1 和 SETBP1 (ICC) 或 SETBP1 ± ETNK1 (WHO) 突变可用于支持诊断。这两种疾病均因粒细胞增殖而显示骨髓细胞增多，aCML 的特点是粒细胞和其他谱系的发育不良。要求不存在单核细胞增多、罕见/无嗜碱性粒细胞增多或嗜酸性粒细胞增多、原始细胞<20%，并排除其他 MPN、MDS/MPN 和酪氨酸激酶融合。约 1/3 的 CNL 患者和约 15-40% 的 aCML 患者发现细胞遗传学异常。 CNL 的分子特征是集落刺激因子 3 受体（典型的 T618I）的驱动突变，在超过 80% 的病例中均有记录。 非典型 CML 具有复杂的基因组背景，ASXL1、SETBP1、TET2、SRSF2、EZH2 中复发性体细胞突变率较高，而 ETNK1 中复发性体细胞突变率较低。 CNL 和 aCML 的白血病转化率分别约为 10-25% 和 30-40%。总生存期很差：CNL 为 15-31 个月，aCML 为 12-20 个月。 Mayo Clinic CNL 生存风险模型根据血小板 <160 × 10 ⁹ /L（2 分）、白细胞 >60 × 10 ⁹ /L（1 分）、 ASXL1 突变（1 分）；区分低风险（0-1 分）和高风险（2-4 分）类别。 Mayo Clinic aCML 风险模型对以下各项分别赋予 1 分：年龄 >67 岁、血红蛋白 <10 g/dL 和 TET2 突变，划分低风险（0-1 个风险因素）和高风险（≥2 个风险因素）亚组。管理是风险驱动和症状导向的，目前没有护理标准。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药物，但都不能缓解疾病。造血干细胞移植是唯一潜在的治愈方式，符合条件的患者应考虑进行治疗。最近的基因分析揭示了 CBL、CEBPA、EZH2、NRAS、TET2 和 U2AF1 代表这两个实体的高风险突变。可操作的突变（NRAS/KRAS、ETNK1）也已被发现，支持针对相关途径的新型药物。详细介绍了评估新药（例如，fedratinib，2 期）和组合的临床前和临床研究。