Ibrutinib, a once-daily inhibitor of Bruton’s tyrosine kinase, is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). After the phase 3 RESONATE-2 trial, ibrutinib received approval as frontline therapy in treatment-naïve patients with CLL. In this study, ibrutinib reduced the risk of progression or death by 84% compared with chlorambucil. In an effort to better understand the mechanism by which these agents act on the immune system, quantitative changes in circulating cells were studied throughout the first year of treatment.
Immunophenotypic analyses were performed on a total of 80 patients to assess lymphoid and myeloid cells of treatment-naïve patients with CLL who received 420 mg ibrutinib once daily (n = 50) or chlorambucil 0.5 to 0.8 mg/kg twice per month (n = 30). The researchers found substantial differences in the immunophenotypic and quantitative impacts of the 2 therapies during the first year of treatment. Ibrutinib mainly reduced B-cells (90%), myeloid-derived suppressor cells (61%), and certain T-cells—specifically, long-term activated T-cells, PD-1+ T-cells, regulatory T-cells, and effector T-cells (27%-52%)—while showing limited effect on naïve T-cells, stem-cell memory T-cells, central memory T-cells, and natural killer (NK) cells. Classical monocytes were increased (+187%), while nonclassical monocytes did not increase. Conversely, chlorambucil progressively reduced circulating B-, T-, NK, and NKT cells, myeloid-derived suppressor cells, and monocytes by 69% to 99%. All development stages of CD4+ and CD8+ T-cells, except stem-cell memory T-cells, decreased by 51% to 90%. Long-term activated T-cells, however, were not affected throughout a full year of treatment with chlorambucil.
The data indicate that ibrutinib targets cells involved in tumor growth, while preserving cells that are important for mounting antitumor responses. Chlorambucil was found to act less specifically than ibrutinib on most immune-cell subsets in circulation. These data help to explain the differential clinical activity and side-effect profiles for ibrutinib and chlorambucil.
Solman I, et al. ASCO Abstract 7524.