Kim Dong Hyun, Kim Seokhyeon, Park Seonyang, Byun Ja Min, Hong Junshik, Shin Dong-Yeop, Kim Inho, Bang Soo Mee, Lee Jeong-Ok, Lee Ji Yun, Kim Sang-A, Kim Ki Hwan, Chung Yeun-Jun, Jung Seung-Hyun, Koh Youngil, Yoon Sung-Soo
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea.
Br J Haematol. 2024 Dec;205(6):2305-2314. doi: 10.1111/bjh.19828. Epub 2024 Oct 10.
The role of imatinib in PDGFRA/B-negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B-negative HES. Thirty-two patients were treated with imatinib (100-400 mg daily), and the molecular basis of their response was identified using whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression-free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non-silent mutations did not differ between responders and non-responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non-responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B-negative HES.
由于嗜酸性粒细胞增多综合征（HES）的异质性以及前瞻性研究的匮乏，伊马替尼在血小板衍生生长因子受体α/β（PDGFRA/B）阴性的HES中的作用存在争议。我们开展了一项II期临床试验，以评估伊马替尼在PDGFRA/B阴性HES中的疗效。32例患者接受伊马替尼治疗（每日100 - 400毫克），并使用全外显子组测序（WES）和全转录组测序（WTS）确定其反应的分子基础。血液学反应率为46.9%，完全血液学缓解（CHR）率为18.8%。中位反应时间为1.5个月。在达到CHR的6例患者中，5例维持至伊马替尼治疗的第24个周期，1例在20个月后失去反应。中位无进展生存期为4.3个月。对11例患者进行了WES和WTS。有反应者和无反应者之间的非沉默突变数量没有差异。包括小核仁RNA15A（SNORD15A）在内的9个差异表达基因在有反应者中下调。在持续有反应的患者中鉴定出信号转导和转录激活因子5B::维甲酸受体α（STAT5B::RARA）、丝氨酸/苏氨酸蛋白激酶2::磷脂酰肌醇聚糖生物合成蛋白X（PAK2::PIGX）和FIP1样蛋白1::CHIC2融合基因，在无反应者中鉴定出环指蛋白130::B-Raf原癌基因（RNF130::BRAF）和富含脯氨酸/丝氨酸的蛋白激酶1::赖氨酸特异性去甲基化酶5A（WNK1::KDM5A）融合基因。伊马替尼联合合适的生物标志物可能是PDGFRA/B阴性HES的一个有前景的选择。
