Immune restoration with ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia: the phase 2 CAPTIVATE study.

We evaluated immune cell subsets in patients with chronic lymphocytic leukemia (CLL) who received first-line therapy with 3 cycles of ibrutinib then 13 cycles of ibrutinib plus venetoclax in the minimal residual disease (MRD) cohort of the CAPTIVATE study (NCT02910583). Patients with confirmed undetectable MRD (uMRD) were randomized to placebo or ibrutinib; patients without confirmed uMRD were randomized to ibrutinib or ibrutinib plus venetoclax. We compared immune cell subsets in cryopreserved peripheral blood mononuclear cells collected at 7 timepoints with age-matched healthy donors; median changes from baseline are reported. CLL cells decreased within 3 cycles after venetoclax initiation and from Cycle 16 onwards were similar to healthy donors (</=0.8 cells/µL) in Confirmed uMRD patients, and slightly above healthy donor levels in patients without Confirmed uMRD. By 4 months after Cycle 16, normal B cells recovered to healthy donor levels in patients randomized to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to healthy donor levels within 6 months (‒49%, +101%, and +91% from baseline, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomized to placebo within 12 months after Cycle 16. Sustained elimination of CLL cells and recovery of normal B cells was confirmed in samples from patients treated with fixed-duration ibrutinib plus venetoclax in the GLOW study (NCT03462719). These results demonstrate promising evidence of restoration of normal blood immune composition with ibrutinib plus venetoclax.