Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
Key Laboratory of Hematology of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
Hematol Oncol. 2019 Oct;37(4):392-400. doi: 10.1002/hon.2667. Epub 2019 Sep 13.
Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4 (P < .01), total CD8 (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4 (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal β2-macroglobulin (β2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal β2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.
伊布替尼是一种第一代布鲁顿酪氨酸激酶（BTK）抑制剂，可改善复发或难治性（R/R）慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）患者的免疫功能。泽布替尼是一种第二代选择性 BTK 抑制剂，其是否具有与伊布替尼相似的作用尚待确定。通过流式细胞术和血常规检查，研究了 25 例 R/R CLL/SLL 患者在接受泽布替尼治疗期间免疫细胞数量和免疫表型的动态变化。治疗后，总 CD4（P<0.01）、总 CD8（P<0.01）和辅助性 T 细胞（P<0.05）上程序性死亡受体-1（PD-1）的表达强度以及总 CD4（P=0.010）和调节性 T 细胞（P<0.05）上细胞毒性 T 淋巴细胞相关抗原-4（CTLA-4）的表达强度降低。治疗前后 B 细胞上 CD19（P<0.01）、C-X-C 趋化因子受体 5（CXCR5）（P<0.01）和 CD49d（P<0.05）的表达强度存在显著差异。在接受泽布替尼治疗后，几乎所有患者的 T 细胞上 PD-1 以及 B 细胞上 CXCR5 和 CD19 的表达均下调。程序性死亡配体 1（PD-L1）的表达下调，尤其是在女性、CLL、正常脾脏、正常β2-微球蛋白（β2-MG）和异常乳酸脱氢酶（LDH）亚组中，而 CD4+T 细胞上 CTLA-4 的表达在男性、年龄较大、CLL、脾肿大、异常β2-MG、正常 LDH、IGHV 突变和野生型肿瘤蛋白 53 亚组中则呈下降趋势。这些发现表明，泽布替尼主要通过改善 T 细胞耗竭、抑制抑制性细胞和破坏 CLL 细胞迁移来调节免疫，其作用机制是通过下调黏附/归巢受体。此外，在无不良预后因素的患者中，细胞数量和免疫表型的有利变化更易观察到。
