The Impacts of Zanubrutinib on Immune Cells in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Abstract

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 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 cell death protein 1 (PD-1) on total CD4+, total CD8+ and T helper cells, and cytotoxic T lymphocyte-associated antigen-4 on total CD4+ (P=0.010) and regulatory T cells (P<0.05) reduced after treatment (P<0.05). There were significant differences in expression intensity of CD19 (P<0.01), C-X-C chemokine receptor type 5 (CXCR5) (P<0.01) and CD49d (P<0.05) on B cells before and after treatment. Down-regulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. The number of B cells and programmed death-ligand 1 expression down-regulated, especially in the young, CLL, normal spleen, normal I²2-macroglobulin (I²2-MG), abnormal lactate dehydrogenase (LDH) and normal tumor protein 53 subgroups, while CD49d expression tended to decrease in the male, old, CLL, splenomegaly, abnormal I²2-MG and abnormal LDH 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 down-regulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors. Funding: This study was supported by National Natural Science Foundation of China (81370657, 81470328, 81470329, 81600130, 81770166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science & Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2018ZX09734-007). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: This study was approved by the hospital ethics committee and all patients were provided informed consent according to the Helsinki Declaration of 1975.