Laboratory Assessment of Patients with Hypereosinophilic Syndrome

除了FIP 1 L1-PDGFRA融合基因的存在外，对临床定义的嗜酸性粒细胞增多综合征（HES）中伊马替尼反应的预测因子知之甚少。 在这项研究中，我们根据FIP 1 L1-PDGFRA突变状态和提示髓系肿瘤的标准对HES患者进行了分层。外周血和骨髓标本在外周血涂片上评价异型增生嗜酸性粒细胞（异常核分叶、不均匀肉芽、肉芽不足、无粒形成）、血清B12水平1000 pg/ml、血清类胰蛋白酶水平12 ng/mL、贫血和/或血小板减少、骨髓细胞构成>80%伴成熟左移、发育异常在骨髓活检中发现（梭形）肥大细胞，在骨髓活检中发现网硬蛋白纤维化2+证据，在骨髓活检中发现发育不良巨核细胞。 将患有FIP 1 L1-PDGFRA-髓样肿瘤（FP; n =12）、具有4项提示髓样肿瘤标准的PDGFRA阴性HES（MHES; n =10）或具有<4项髓样肿瘤标准的类固醇难治性PDGFRA阴性HES（SR; n = 5）的受试者纳入伊马替尼治疗的前瞻性研究。主要结局是1个月时嗜酸性粒细胞计数<1.5 × 109/L和临床症状改善。评估了伊马替尼的临床、分子和骨髓反应。此外，根据前瞻性研究中使用的标准，对18例接受伊马替尼（每日300-400 mg，1个月）治疗的临床定义的HES受试者的回顾性队列进行分类。 总体结果显示，FP组（n = 16）、MHES组（n = 13）和SR组（n = 16）的伊马替尼缓解率分别为100%、54%和0%。存在4种骨髓特征是缓解的唯一预测因素。完全缓解18个月后，8例FP和1例MHES受试者逐渐减少伊马替尼剂量并停用。7例受试者（6例FP，1例MHES）在停止治疗后仍处于缓解状态，中位时间为29个月（范围14-36）。 总之，MHES的临床特征可预测伊马替尼在PDGFRA阴性HES中的反应。

With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). In this study, we have stratified HES patients according to their FIP1L1-PDGFRA mutational status and criteria suggestive of a myeloid neoplasm. The peripheral blood and bone marrow specimens were evaluated for dysplastic eosinophils on peripheral smear (abnormal nuclear lobation, uneven granulation, hypogranulation, agranulation), serum B12 level 1000 pg/ml, serum tryptase level 12 ng/mL, anemia and/or thrombocytopenia, bone marrow cellularity >80% with left shift in maturation, dysplastic (spindle-shaped) mast cells on bone marrow biopsy, evidence of reticulin brosis 2+ on bone marrow biopsy, and dysplastic megakaryocytes on bone marrow biopsy. Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with 4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy. The primary outcome was an eosinophil count <1.5 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. In addition, a retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily 1 month) were classified according to the criteria used in the prospective study. Overall results showed that imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of 4 myeloid features was the sole predictor of response. After 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remained in remission off therapy for a median of 29 months (range 14-36). In conclusion, clinical features of MHES predict imatinib response in PDGFRA-negative HES.