Impact of long-term ibrutinib treatment on circulating immune cells in previously untreated chronic lymphocytic leukemia

•Ibrutinib preferentially reduced malignant B cells over normal B cells.•Ibrutinib reduced and normalized counts of immunosuppressive cells.•Ibrutinib treatment restored circulating counts of plasmacytoid dendritic cells.•Ibrutinib continuously exerted positive effects on immune cell subsets over 4 years. This study evaluated long-term immunophenotypic changes in circulating levels of 24 immune cell subsets through 4 years of continuous treatment with first-line ibrutinib (420 mg once daily) in 31 patients with chronic lymphocytic leukemia (CLL) from the RESONATE-2 study, and compared them with untreated age-matched healthy donors (n = 20). Ibrutinib progressively decreased total B-cell counts and preferentially targeted malignant CLL B cells over normal B cells. Elevated counts of chronically activated, exhausted, and effector memory T cells were normalized within 6–16 months, while naive T cells remained mostly within healthy donor range (HDR). Immunosuppressive regulatory T cells and myeloid-derived suppressor cells were normalized within the first 1–2 years and then plateaued. Additionally, ibrutinib restored low counts of innate cell populations associated with antitumor immunity: plasmacytoid dendritic cells were restored to HDR after 2 years, and classical monocyte counts progressively and continuously increased toward HDR. Ibrutinib also consistently preserved circulating mature natural killer cell counts. The data indicate that ibrutinib continuously exerted positive effects on immune cell populations throughout 4 years of treatment, consistent with improved clinical outcomes observed in patients. The normalization of adaptive and innate immune cell populations suggests that long-term ibrutinib treatment mediates restoration of immunity.