Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial.

BACKGROUND

Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group.

METHODS

HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (<10

FINDINGS

Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34·4 months (IQR 30·6-37·9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89-100). Infections (in 130 [58%] of 225 patients), neutropenia (in 91 [40%] patients), and gastrointestinal adverse events (in 53 [24%] patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib.

INTERPRETATION

These data point to a favourable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population.

FUNDING

AbbVie and Janssen.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests APK reports research grants from Celgene, Janssen, AbbVie, Roche/Genentech, and AstraZeneca; speakers fees from AbbvVie and AstraZeneca; and participation in advisory boards of AbbVie, Janssen, AstraZeneca, and Roche. M-DL reports advisory board compensation from Janssen, AbbVie, and Roche; and travel reimbursement from Janssen, AbbVie, and Roche. JD reports research funding from Roche/Genentech. MM reports lecture remuneration from Janssen and advisory board compensation from AbbVie. SK reports fees from Janssen, AbbVie, and Celgene; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. JR reports consultancy fees from AbbVie, Janssen, and AstraZeneca. CB reports honoraria from AstraZeneca and Octapharma outside this study. HF reports consultancy fees from AstraZeneca, Janssen, Novartis, and Sanofi; participation in advisory boards for AstraZeneca, Janssen, Sobi, Novartis, Sandoz, Merck Sharp & Dohme, Incyte, and Beigene; and speaker fees from AstraZeneca, Janssen, Sobi, Incyte, Novartis, AbbVie, Amgen, Takeda, and Beigene. HF reports research grants from Sanofi and Novartis and honoraria for lectures from Sanofi. HTTT reports consultancy fees from Janssen-Cilag, AbbVie, Bayer, Novartis, and AstraZeneca. CUN reports research grants from AbbVie and Janssen; advisory board compensation from AbbVie, Janssen, Gilead, Roche, AstraZeneca, Acerta, and Sunesis; travel reimbursement from Gilead, Roche, and Novartis; and consultancy compensation from CSL Behring. All other authors declare no competing interests.