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.

Conflict of interest statement

Othman Al-SawafHonoraria: Janssen-Cilag, Roche, Gilead Sciences, AbbVie, AstraZeneca, Adaptive Biotechnologies, BeiGeneConsulting or Advisory Role: Roche, Janssen-Cilag, Gilead Sciences, AbbVieResearch Funding: BeiGene (Inst), Roche (Inst), AbbVie (Inst), Janssen/Pharmacyclics (Inst)Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen-Cilag Tong LuEmployment: Genentech/RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: P36418-US Title: Methods and systems for placebo response modeling Michael Z. LiaoEmployment: Genentech/RocheStock and Other Ownership Interests: Roche, Amgen Anesh PanchalEmployment: Genentech/Roche Travers ChingEmployment: Adaptive BiotechnologiesStock and Other Ownership Interests: Adaptive Biotechnologies Maneesh TandonEmployment: Roche (I)Stock and Other Ownership Interests: Roche Pharma AG Anna-Maria FinkResearch Funding: Celgene/Bristol Myers Squibb (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AbbVie Eugen TauschConsulting or Advisory Role: Roche, AbbVieSpeakers' Bureau: Roche, AbbVie, Janssen-CilagTravel, Accommodations, Expenses: AbbVie Matthias RitgenHonoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, MSDConsulting or Advisory Role: AbbVie, Roche, AstraZenecaResearch Funding: Roche (Inst), AbbVie (Inst)Patents, Royalties, Other Intellectual Property: Partial patent holder, only intellectual propertyTravel, Accommodations, Expenses: AstraZeneca, Takeda Sebastian BöttcherHonoraria: Roche, AbbVie, AstraZeneca, Janssen, SanofiConsulting or Advisory Role: AstraZeneca, JanssenResearch Funding: Janssen (Inst) Karl-Anton KreuzerHonoraria: Roche, AbbVieConsulting or Advisory Role: Roche, AbbVieSpeakers' Bureau: Roche, AbbVieResearch Funding: Roche (Inst), AbbVie (Inst)Expert Testimony: Roche, AbbVieTravel, Accommodations, Expenses: Roche, AbbVie Brenda ChylaEmployment: AbbVieStock and Other Ownership Interests: AbbVie Dale MilesEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: Genentech Clemens-Martin WendtnerHonoraria: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesConsulting or Advisory Role: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesResearch Funding: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesTravel, Accommodations, Expenses: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences Barbara EichhorstHonoraria: Roche, AbbVie, Gilead Sciences, Janssen, Novartis, Hexal, AstraZeneca, Adaptive Biotechnologies, Oxford Biomedica, Miltenyi BiotecConsulting or Advisory Role: Gilead Sciences, Janssen-Cilag, Roche, AbbVie, Novartis, Celgene, AstraZeneca, ArQuleSpeakers' Bureau: Roche/Genentech, Janssen-Cilag, Gilead Sciences, Celgene, AbbVie, NovartisResearch Funding: Roche, AbbVie, Gilead Sciences, Janssen, Beijing Genomics InstituteTravel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen Stephan StilgenbauerHonoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenConsulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenSpeakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenResearch Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenTravel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen Yanwen JiangEmployment: GenentechStock and Other Ownership Interests: Genentech Michael HallekHonoraria: Roche, Janssen, AbbVie, Gilead Sciences, AstraZenecaConsulting or Advisory Role: Janssen, AbbVie, Gilead Sciences, Genentech/Roche, AstraZenecaSpeakers' Bureau: Janssen, AbbVie, Gilead Sciences, Roche/Genentech, AstraZenecaResearch Funding: Roche (Inst), AbbVie (Inst), Janssen (Inst), Gilead Sciences (Inst), AstraZeneca (Inst), Travel, Accommodations, Expenses: Roche, Janssen Kirsten FischerHonoraria: AbbVie, RocheConsulting or Advisory Role: AbbVie, RocheTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Figures

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.