Williams Lewis J, Li-Wai-Suen Connie Sn, Garnham Alex L, Bader Stefanie M, Tam Constantine S, Whitechurch Ashley, Slavin Monica A, Doerflinger Marcel, Teh Benjamin W
The Walter and Eliza Hall Institute for Medical Research Parkville VIC Australia.
Department of Medical Biology The University of Melbourne Melbourne VIC Australia.
Clin Transl Immunology. 2025 Aug 3;14(8):e70049. doi: 10.1002/cti2.70049. eCollection 2025.
Chronic lymphocytic leukaemia (CLL) patients are at increased risk for infection, with the risk even higher for relapsed and refractory patients. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapies, such as Bruton's tyrosine kinase inhibitors. A pilot study was conducted to elucidate possible predictive immune markers.
Patients with relapsed and refractory CLL treated with ibrutinib were evaluated. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals (baseline, 3- and 6 months following commencement of ibrutinib) were analysed, with or without phorbol myristate acetate (PMA)/ionomycin stimulation, using Luminex and RNA sequencing. Luminex and gene expression profiles were compared between patients that who did and did not develop infection to identify immune signatures associated with infection over a subsequent 3-month period.
Twenty-eight patients were included in this pilot study. Forty-six per cent of patients developed an infection (13 patients, 17 events) over 9 months of patient monitoring. Most infections were clinically diagnosed (72.7%) with the remainder microbiologically diagnosed bacterial (18.1%) and viral (9.2%) infections. Cell populations did not correlate with subsequent infection. An inflammatory transcriptome profile at 3 months following ibrutinib was associated with a subsequent infection episode. Increased whole protein response to PMA stimulation at 3 and 6 months was associated with subsequent risk for infections. Increased whole protein response to PMA stimulation was associated with subsequent risk of infection 3 months after commencing ibrutinib.
The combination of protein and RNA analysis can provide further insight into the interactions of immunotherapies and immunity but should be validated further in large cohorts.
慢性淋巴细胞白血病（CLL）患者感染风险增加，复发和难治性患者的风险更高。在基于免疫的疗法（如布鲁顿酪氨酸激酶抑制剂）时代，感染风险的临床评估越来越具有挑战性。开展了一项试点研究以阐明可能的预测性免疫标志物。
对接受依鲁替尼治疗的复发和难治性CLL患者进行评估。在规定时间间隔（基线、依鲁替尼开始治疗后3个月和6个月）采集外周血单个核细胞（PBMC），使用Luminex和RNA测序分析，有或无佛波酯肉豆蔻酸酯乙酸酯（PMA）/离子霉素刺激。比较发生和未发生感染患者之间的Luminex和基因表达谱，以识别随后3个月内与感染相关的免疫特征。
本试点研究纳入了28例患者。在9个月的患者监测期间，46%的患者发生了感染（13例患者，17次感染事件）。大多数感染通过临床诊断（72.7%），其余为微生物学诊断的细菌感染（18.1%）和病毒感染（9.2%）。细胞群体与随后的感染无关。依鲁替尼治疗3个月时的炎症转录组谱与随后的感染发作相关。在3个月和6个月时对PMA刺激的全蛋白反应增加与随后的感染风险相关。开始依鲁替尼治疗3个月后，对PMA刺激的全蛋白反应增加与随后的感染风险相关。
蛋白质和RNA分析相结合可以进一步深入了解免疫疗法与免疫的相互作用，但应在大型队列中进一步验证。
