Ibrutinib Treatment Improves T-Cell Proliferative Ability and Effector Function in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.3114-3114
• Main Authors: Solman, Isabelle G., Taylor, Marlene, You, Hana, O'Brien, Susan M., Mulligan, Stephen P., Byrd, John C., Dean, James P., James, Danelle F., Mongan, Ann
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-110848

Background: CLL is a B-cell malignancy characterized by profound immune dysregulation, including dysfunctional T cells. Ibrutinib (ibr), a first-in-class, once-daily BTK inhibitor, is approved in the US for the treatment of CLL/SLL, and has been reported to additionally inhibit ITK in T cells. Previous studies showed that ibr has a positive impact on T-cell compartments by decreasing abnormally elevated regulatory T cells and pseudo-exhausted effector T cells, while preserving naive T-cell counts post 1 year of treatment (Solman ASH Lymphoma 2016; Solman ASCO 2017). Moreover, lower infection rates have been reported following 6 months of ibr treatment, suggesting that ibr might restore T-cell functions over time (Long JCI 2017). To further assess the effects of ibr on T-cell function, we evaluated the ability of cells to proliferate, degranulate, and release cytokines upon stimulation. Methods: Samples for this study were derived from patients (pts) with relapsed/refractory CLL enrolled in the RESONATE™ trial (Byrd NEJM 2014). In the 2 treatment arms, ibr and ofatumumab (ofa), we compared responders (PR) and non-responders (SD) per investigator assessment at week (wk) 24 - end of ofa treatment - to isolate the treatment effect on T cells. In total, we selected 19 pts wk1 through wk48 from ibr arm (420 mg once daily; 12 PR & 7 SD at wk24) and 21 pts wk1 through wk24 from ofa arm (300 mg once followed by weekly 2000 mg; 10 PR & 11 SD at wk24). Also included in the study for reference were 18 untreated, age-matched healthy donors. Cryopreserved PBMCs were immunophenotyped before and after 4-day in vitro stimulation with anti-CD3/CD28. T-cell proliferation was measured with CFSE staining, while secreted lytic proteins and cytokines were measured by bead-based immunoassays. Unless specified otherwise, median changes at wk24 relative to baseline (wk1) are reported. Results: Compared to reference range (ref) of healthy donors, all CLL samples were found to have higher percentage of apoptotic T cells. We further evaluated the fraction of apoptotic T cells in each treatment arm. In the treated CLL patients, a larger decrease in the apoptotic fraction was observed in vivo with ibr (46%) compared to ofa (24%). To evaluate how well T cells were able to respond to stimulation, we assessed T-cell death post in vitro stimulation. In vitro, both treatments were found to reduce cell death, with ofa exerting an earlier effect on apoptosis (57% for ofa vs 17% for ibr at wk24