Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study

Abstract

Purpose: The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study.

Patients and methods: Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed.

Results: Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10^-6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred.

Conclusion: Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi-treated patients remaining in remission.

Trial registration: ClinicalTrials.gov NCT02242942.

FIG 1.

Follow-up month 3 (ie, 2 months after treatment completion) minimal residual disease status by next-generation sequencing on the basis of intention-to-treat population. Clb-Obi, chlorambucil-obinutuzumab; MRD, minimal residual disease; NE, not evaluable; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.

FIG 2.

(A) Sankey plot for MRD levels by NGS between cycle 7 and FUm3 (ie, 2 months after treatment completion) in the Ven-Obi arm (patients during Ven-Obi treatment). (B) Waterfall plot for the 14 patients with detectable MRD (≥ 10⁻⁴) at FUm3 in the Ven-Obi arm and available MRD assessment at cycle 7 by NGS, with each bar representing absolute log changes from cycle 7 to FUm3 per patient. FUm3, follow-up month 3; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; NGS, next-generation sequencing; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.

FIG 3.

(A) Model calibration for (left) Clb-Obi and (right) Ven-Obi arms. (B) Time to MRD doubling and (C) time to MRD 10⁻² in days, predicted by the growth model. (D) Time to MRD conversion (≥ 10⁻⁴) according to the treatment arm, from EoT. (E) Time to MRD conversion (≥ 10⁻⁴) according to the treatment arm and BM MRD status, from EoT. (F) PFS according to BM MRD status, from last treatment exposure. BM, bone marrow; Clb-Obi, chlorambucil-obinutuzumab; EoT, end of treatment; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; PFS, progression-free survival; uMRD, undetectable minimal residual disease; Ven-Obi, venetoclax-obinutuzumab.

FIG 4.

Sankey plot showing MRD levels, measured by next-generation sequencing, from baseline to latest FU visit in the (A) Ven-Obi (n = 216) and (B) Clb-Obi (n = 216) arm. Percentages are provided in relation to the intention-to-treat population. Clb-Obi, chlorambucil-obinutuzumab; FU, follow-up; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.

FIG 5.

Kaplan-Meier analyses for PFS according to (A) the study arm, (B) status of TP53 aberrations and study arm, and (C) IGHV status and study arm. Clb-Obi, chlorambucil-obinutuzumab; OS, overall survival; PFS, progression-free survival; Ven-Obi, venetoclax-obinutuzumab.

FIG 6.

Kaplan-Meier analysis for (A) TTNT per study arm and (B) OS per study arm. Clb-Obi, chlorambucil-obinutuzumab; OS, overall survival; TTNT, time to next anti-leukemic treatment; Ven-Obi, venetoclax-obinutuzumab.