We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HE_US used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87–13.13]; p = .001), anemia (HR 5.50 [2.24–13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39–19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new “gene mutated-entity” that could be differentiated from CEL, NOS, and idiopathic HES.

中文翻译：

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JAK-STAT 通路参与酪氨酸激酶融合阴性嗜酸性粒细胞增多综合征的分子景观：一项全国性 CEREO 研究

我们使用包含 149 个基因的定制 NGS 面板，研究了 64 名连续成年患者的突变情况，这些患者患有酪氨酸激酶融合阴性嗜酸性粒细胞增多症 (HE)/嗜酸性粒细胞增多综合征 (HES)，具有提示骨髓肿瘤的特征。 50/64 (78%) 的患者报告至少一种突变（相比之下，8/44 (18%) 的特发性 HE/HES/HE _US患者用作对照；p  < .001）。 35 名患者（54%）至少有 1 个涉及 JAK-STAT 通路的突变，包括STAT5B（n  = 18，其中热点 N642H，n  = 13）、JAK1（外显子 13 插入缺失，n  = 5；V658F） /L，n  = 2) 和JAK2 (V617F，n  = 6；外显子 13 中的插入缺失，n  = 2)。在JAK2、JAK1、STAT5B和STAT5A中还发现了其他先前未描述的体细胞突变，包括三名具有相同STAT5A V707fs 突变和与原发性红细胞增多症一致的特征的患者。几乎所有 JAK-STAT 突变都发生在骨髓增生异常相关基因突变之前（或与之相关），尤其是 RNA 剪接基因或染色质修饰基因突变。在多变量分析中，神经系统受累（风险比 [HR] 4.95 [1.87–13.13]；p  = .001）、贫血（HR 5.50 [2.24–13.49]；p  < .001）以及存在高风险突变（根据分子国际预后评分系统：HR 6.87 [2.39–19.72]；p  < .001）与总生存期受损独立相关。虽然皮质类固醇对所有治疗的 JAK-STAT 突变患者均无效，但鲁索替尼显示出阳性血液学反应，包括STAT5A突变患者。这些发现强调了 NGS 对于酪氨酸激酶融合阴性 HE/HES 患者检查的有用性，并支持在这种情况下使用 JAK 抑制剂。更新的分类可以将具有 JAK-STAT 突变和嗜酸性粒细胞增多的患者视为新的“基因突变实体”，可以与 CEL、NOS 和特发性 HES 区分开来。