Objective: To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL).
Methods: The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively.
Results: The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively.
Conclusions: BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.
题目: 慢性淋巴细胞白血病BTKi治疗后免疫功能重建研究.
目的: 分析慢性淋巴细胞白血病（CLL）经布鲁顿酪氨酸激酶抑制剂（BTKi）治疗后的免疫功能重建情况。.
方法: 收集2017年1月至2022年3月在福建医科大学附属协和医院血液科就诊的59例CLL患者的病历信息，对其诊断、治疗和实验室检查资料进行回顾性分析研究。.
结果: 59例CLL患者中位年龄为60.5（36-78）岁；BTKi治疗1年后，51例（86.4%）的CLL肿瘤克隆（CD5+/CD19+）明显缩小，治疗前后分别为（46±6.1）×109/L和（2.3±0.4）×109/L（P =0.0013），而非肿瘤克隆（CD19+减去CD5+/CD19+）无明显变化；免疫球蛋白IgA明显升高，治疗前后分别为（0.75±0.09）g/L和（1.31±0.1）g/L（P <0.001），但IgG和IgM下降，分别为（8.1±0.2）g/L和（7.1±0.1）g/L（P <0.001）、（0.52±0.6）g/L和（0.47±0.1）g/L（P =0.002）。BTKi治疗前后CLL患者的T细胞亚群出现明显变化，表现为总T细胞数从（2.1±0.1）×109/L减少至（1.6±0.4）×109/L（P =0.042），CD4+细胞数从（0.15±6.1）×109/L增加至（0.19±0.4）×109/L（P <0.001），CD8+细胞数从（0.27±0.01）×109/L增加至（0.41±0.08）×109/L（P <0.001），NK/T细胞数从（0.11±0.1）×109/L下降至（0.07±0.01）×109/L（P =0.038）；白细胞介素（IL）-2表达上调、IL-4和干扰素γ表达下降，但IL-6、IL-10、肿瘤坏死因子α表达变化不大；TCR和BCR组库多样性都得到恢复，完全缓解患者比部分缓解患者恢复更明显，完全缓解患者BTKi治疗前后TCR组库香农指数分别为0.02±0.008和0.14±0.01（P <0.001），部分缓解患者分别为0.01±0.03和0.05±0.02（P >0.05），而BCR组库香农指数分别是0.19±0.003和0.33±0.15（P <0.001）、0.15±0.009和0.23±0.18（P <0.05）。.
结论: BTKi治疗可以缩小CLL克隆，促进IgA表达，增加功能性T细胞数量，调节IL-2、IL-4、干扰素γ等分泌，改善肿瘤微环境的免疫调节状态；BTKi治疗还能促进TCR和BCR免疫组库多样性的恢复。BTKi治疗有助于CLL患者的免疫功能重建。.
Keywords: Bruton’s tyrosine kinase inhibitor; chronic lymphocytic leukemia; immune reconstitution; retrospective study.