Marginal zone lymphoma is associated with dysregulated T-cell immunity that is not altered by ibrutinib-venetoclax...

Marginal zone lymphoma (MZL) is a rare non-Hodgkin lymphoma. We recently reported that treatment with ibrutinib-venetoclax under the phase 2 AIM study resulted in an overall response rate of 79%. In the current study, we analyzed the immunology of MZL and the effect of ibrutinib-venetoclax treatment. Peripheral blood mononuclear cell samples from 14 patients with relapsed/refractory MZL were collected over 2 years as part of a preplanned analysis. Immune profile was assessed using spectral flow cytometry and functional assays and compared to age-matched healthy donors. Results were correlated with centrally determined positron emission tomography/computed tomography response. Patients with MZL exhibited normal proportions of monocytes, myeloid-derived suppressor cells, and myeloid dendritic cells, with reduced proportions of plasmacytoid dendritic cells (P < .01). Although there was no difference in total proportions of CD4 or CD8 T cells or natural killer (NK) cells at baseline, there was skewing of memory subsets with upregulation of programmed cell death 1 protein (PD-1) on T cells and TIM3 on NK cells. T-cell production of interferon gamma, tumor necrosis factor α, and CD107a was increased sixfold (P < .001), which did not reduce with treatment. Mature NK cell degranulation was elevated at baseline (P < .05) and decreased with treatment. Complete response to treatment was associated with maintenance or expansion of TIM3⁺ mature NK cells (P < .05). To our knowledge, this is the first study to examine peripheral blood immunology in MZL as a single disease group. Given the lack of T-cell repair, immunotherapy protocols using ibrutinib may be less effective in MZL. This trial was registered at www.clinicaltrials.gov as #NCT02471391.