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Clinical Trial
. 2023 Sep 26;7(18):5294-5303.
doi: 10.1182/bloodadvances.2023010236.

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

Carol Moreno  1 , Isabelle G Solman  2 , Constantine S Tam  3 , Andrew Grigg  4 , Lydia Scarfò  5 , Thomas J Kipps  6 , Srimathi Srinivasan  7 , Raghuveer Singh Mali  2 , Cathy Zhou  2 , James P Dean  2 , Edith Szafer-Glusman  2 , Michael Choi  8
Affiliations
Clinical Trial

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

Carol Moreno et al. Blood Adv. .

Abstract

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 randomly assigned to placebo or ibrutinib groups; patients without Confirmed uMRD were randomly assigned to ibrutinib or ibrutinib plus venetoclax groups. We compared immune cell subsets in samples collected at 7 time points with age-matched healthy donors. CLL cells decreased within 3 cycles after venetoclax initiation; from cycle 16 onward, levels were similar to healthy donor levels (HDL; ≤0.8 cells per μL) in patients with Confirmed uMRD and slightly above HDL in patients without Confirmed uMRD. By 4 months after cycle 16, normal B cells had recovered to HDL in patients randomly assigned to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to HDL within 6 months (median change from baseline -49%, +101%, and +91%, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomly assigned to placebo within 12 months after cycle 16. Sustained elimination of CLL cells and recovery of normal B cells were 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.

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Conflict of interest statement

Conflict-of-interest disclosure: C.M. reports a consulting/advisory role with AbbVie, AstraZeneca, Janssen, and Sunesis; research funding from AbbVie and Janssen; and speakers’ bureau for Janssen. I.G.S., R.S.M., C.Z., J.P.D., and E.S.-G. report employment with Pharmacyclics LLC, an AbbVie Company, and stock or other ownership in AbbVie. C.S.T. reports honoraria from AbbVie, BeiGene, Janssen, and Loxo, and institutional research funding from AbbVie, BeiGene, and Janssen. A.G. reports a consulting/advisory role for Janssen and Novartis. L.S. reports honoraria from and a consulting/advisory role for AbbVie, AstraZeneca, BeiGene, Lilly, and Janssen; travel/accommodations/expenses from BeiGene and Janssen; and a speakers’ bureau role for Octapharma. T.J.K. reports a consulting/advisory role for AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company, and research funding from AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company. S.S. reports employment with Janssen. M.C. reports a consulting/advisory role for Genentech, and institutional research funding from AbbVie, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CAPTIVATE MRD cohort study design and disposition of patients included in the immunophenotyping study. C, cycle.
Figure 2.
Figure 2.
Ibrutinib plus venetoclax rapidly eradicates CLL cells. (A) Absolute counts of circulating CLL cells in CAPTIVATE. (B) Absolute counts of normal B cells in CAPTIVATE. (C) Ratio of absolute counts of normal B cells to CLL cells in CAPTIVATE. (D) Absolute counts of circulating CLL cells in GLOW. (E) Absolute counts of normal B cells in GLOW. Data points represent median values, and error bars represent the interquartile range. For GLOW data, samples at cycle 28 were available only for patients with a best overall response of complete response (n = 6 per arm). C+O, chlorambucil plus obinutuzumab; I+V, ibrutinib plus venetoclax; Ibr, ibrutinib; IQR, interquartile range; Tx, treatment.
Figure 3.
Figure 3.
Ibrutinib plus venetoclax normalizes abnormal T-cell counts to healthy donor levels within the first 6 months of treatment. (A) Absolute counts of regulatory T cells. (B) Absolute counts of LTA T cells. (C) Absolute counts of PD-1+ T cells. (D) Absolute counts of γδ T cells. Data points represent median values, and error bars represent the IQR.
Figure 4.
Figure 4.
Ibrutinib plus venetoclax drives recovery of classic monocytes and conventional DCs. (A) Absolute counts of classic monocytes. (B) Absolute counts of nonclassic monocytes. (C) Absolute counts of conventional DCs. (D) Absolute counts of plasmacytoid DCs. Data points represent median values, and error bars represent the IQR.
See this image and copyright information in PMC

References

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