Background: Zanubrutinib (BGB-3111) is a specific and irreversible inhibitor of Bruton’s tyrosine kinase (BTK) exerting a more selective relative inhibition of BTK than ibrutinib. The off-target effects of zanubrutinib are therefore expected to be more limited. Changes in T cells have been observed during long-term treatment with ibrutinib in chronic lymphocytic leukemia (CLL) patients. However, it is unclear whether these are induced by interleukin-2-inducible T-cell kinase (ITK) inhibition or reduced tumor burden.
Aims: To analyse T-cells during treatment with zanubrutinib in patients (pts) with CLL up to 2-years follow-up so to further understand the relative impact of ITK inhibition on the observed changes.
Methods: Peripheral blood (PB) samples were collected before treatment start and at week (wk) 4, 8, 12, 16, 24 and at 8, 12 and 24 months (mo) from 8 treatment naïve (TN) pts included in the BGB-3111-304 and 8 relapsed/refractory (R/R) pts in the BGB-3111-305 clinical trials. Nine healthy individuals were included as controls. Peripheral blood mononuclear cells (PBMC) populations were assessed by flow-cytometry including CLL cells, T-cell memory subsets, helper subpopulations (Ths) and regulatory T cell (Tregs) subsets.
Results: At a 24 mo follow-up, 6/8 pts in the BGB-304 and in the BGB-305 trial were still on treatment and had achieved partial response. Treatment discontinuation was due to: death (n=1), disease progression/Richter transformation (n=1) for the BGB-304 and toxicity (n=1), acute myeloid leukemia (n=1) for the BGB-305. All the pts stayed on full-dose zanubrutinib during the whole treatment period.
As expected, a gradual reduction of the number of CD19+ cells occurred, significant (p<0,05) from mo 8 in both R/R and TN pts. In both groups, CD8+ cell numbers were higher compared to controls at baseline and significantly decreased for R/R pts at wk 16 (p=0.02) and TN at 12 mo (p=0,02). In TN pts, CD8+ cell numbers had not normalized at 24 mo while normalization was seen at 24 mo in R/R pts (Fig. 1A,F). CD4+ cell numbers gradually decreased and normalized in R/R at wk 12 and in TN at 8 mo (Fig. 1B,G). The number of cells expressing the immune checkpoints PD-1 and CTLA-4, which was high on CD4+ and CD8+ cells at baseline, gradually decreased during the treatment.
Among the helper subsets, Th1 (CCR6-/ CXCR3+) cell numbers were higher at baseline compared to controls (p=0.0003), while Th2 (CCR6-/ CXCR3-) did not significantly differ (Fig.1C-D,H-I). In the TN group, Th1 cell numbers never decreased to normal levels (Fig.1H). The Th1/Th2 ratio was significantly higher than in controls at baseline and did not normalize at mo 24 in both groups (Fig.1E,J). There was no significant difference in Th17 (CCR6+/ CXCR3-) cell numbers between pts and controls at baseline and no decrease occurred during treatment. Treg numbers decreased in both groups, in the R/R pts from wk 12 and in TN pts at 12 mo and normalized to the levels of the controls, at wk 24 and 8 mo, respectively.
Summary/Conclusion: During long-term zanubrutinib therapy, both CD8+ and CD4+ cells decreased in number. The expression of PD-1 and CTLA-4 on T cells also decreased. Th1 cell numbers significantly decreased while Th2 remained steady, causing Th2 skewing. This is in line with what previously observed in ibrutinib-treated patients, suggesting that the reduction of the tumor burden rather than ITK inhibition drives changes in the T-cell profile of CLL patients treated with BTK-inhibitors.
Keywords: Bruton’s tyrosine kinase inhibitor (BTKi), B cell chronic lymphocytic leukemia, Immune reconstitution