Shen Yi-Ge, Shi Qing, Tang Wei, Xu Peng-Peng, Cao Yi-Wen, Ji Meng-Meng, Zheng Zhong, Cheng Shu, Wang Li, Zhao Wei-Li
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics; National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
Signal Transduct Target Ther. 2025 Jul 26;10(1):232. doi: 10.1038/s41392-025-02316-6.
Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zanubrutinib for MCD-like and BN2-like, R-ICE-lenalidomide for N1-like and NOS, R-ICE-decitabine for TP53, R-ICE-chidamide for EZB-like, and R-ICE-tofacitinib for ST2-like subtype. Enrolled patients were treated with assigned regimens for three cycles, and then responders were treated with autologous hematopoietic stem cell transplantation (ASCT) or 3 cycles of R-ICE-X consolidation and lenalidomide maintenance. The primary endpoint was the complete response (CR) rate. The secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Between April 26, 2022, and July 31, 2024, 76 patients were enrolled, with 74 adhering to and 2 deviating from the protocol. Among all, the CR rate was 56.6% (95% CI, 45.2-68.0%), and the ORR was 76.3% (95% CI, 66.5-86.1%) at the end of induction. With a median follow-up of 19.5 months, the 2-year PFS rate was 69.3% (95% CI, 56.6-79.0%), and the 2-year OS rate was 88.3% (95% CI, 77.6-94.0%). The primary grade 3-4 adverse events were neutropenia (30%) and thrombocytopenia (25%). The presence of bulky disease and CD70 mutation was linked to poor prognosis. Further gene set enrichment analysis revealed that up-regulated PI3K-AKT-mTOR signaling pathway and reduced immune cell infiltration were significantly associated with disease progression. Patients with mesenchymal or inflammatory lymphoma microenvironment subtypes benefited from R-ICE-X treatment. Our findings highlight the efficacy and safety of R-ICE-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in R/R DLBCL.
改善复发或难治性弥漫性大B细胞淋巴瘤（R/R DLBCL）的治疗结果仍是一项未满足的需求。这项单中心2期试验的目的是评估基因亚型指导的免疫化学疗法（R-ICE-X）在R/R DLBCL患者中的疗效和安全性：针对MCD样和BN2样亚型使用R-ICE-泽布替尼，针对N1样和NOS亚型使用R-ICE-来那度胺，针对TP53亚型使用R-ICE-地西他滨，针对EZB样亚型使用R-ICE-西达本胺，针对ST2样亚型使用R-ICE-托法替布。入组患者接受指定方案治疗三个周期，然后缓解者接受自体造血干细胞移植（ASCT）或3个周期的R-ICE-X巩固治疗及来那度胺维持治疗。主要终点是完全缓解（CR）率。次要终点包括总缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）和安全性评估。在2022年4月26日至2024年7月31日期间，76例患者入组，74例遵守方案，2例偏离方案。总体而言，诱导结束时CR率为56.6%（95%CI，45.2 - 68.0%），ORR为76.3%（95%CI，66.5 - 86.1%）。中位随访19.5个月，2年PFS率为69.3%（95%CI，56.6 - 79.0%），2年OS率为88.3%（95%CI，77.6 - 94.0%）。主要的3 - 4级不良事件是中性粒细胞减少（30%）和血小板减少（25%）。大包块疾病和CD70突变的存在与不良预后相关。进一步的基因集富集分析显示，PI3K - AKT - mTOR信号通路上调和免疫细胞浸润减少与疾病进展显著相关。间充质或炎性淋巴瘤微环境亚型的患者从R-ICE-X治疗中获益。我们的研究结果突出了R-ICE-X这种基于机制的个体化疗法在R/R DLBCL中针对基因和微环境改变的疗效和安全性。
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