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Clinical Trial
. 2025 Aug 12;9(15):3665-3675.
doi: 10.1182/bloodadvances.2024015180.

Long-term follow-up of MRD-guided ibrutinib plus venetoclax in relapsed CLL: phase 2 VISION/HO141 trial

Carsten U Niemann  1 , Julie Dubois  2 , Kazem Nasserinejad  3 , Caspar da Cunha-Bang  1 , Sabina Kersting  4 , Lisbeth Enggaard  1 , Gerrit J Veldhuis  5 , Rogier Mous  6 , Clemens H M Mellink  7 , Anne-Marie F van der Kevie-Kersemaekers  8 , Johan A Dobber  9 , Christian B Poulsen  10 , Wida Razawy  3 , René Hollestein  3 , Henrik Frederiksen  11 , Ann Janssens  12 , Ida Schjødt  1 , Ellen C Dompeling  13 , Juha Ranti  14 , Christian Brieghel  1 , Mattias Mattsson  15 , Mar Bellido  16 , Hoa T T Tran  17 , Arnon P Kater  3 , Mark-David Levin  18
Affiliations
Clinical Trial

Long-term follow-up of MRD-guided ibrutinib plus venetoclax in relapsed CLL: phase 2 VISION/HO141 trial

Carsten U Niemann et al. Blood Adv. .

Abstract

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) are treated with fixed-duration B-cell lymphoma 2 inhibitors + CD20 monoclonal antibodies or continuous Bruton tyrosine kinase (BTK) inhibitors. Although continuous treatment may lead to cumulative toxicity or resistance, fixed-duration treatment may lead to undertreatment and early relapse. Efficacy and safety of minimal residual disease (MRD)-guided treatment cessation of ibrutinib + venetoclax (I+V) with reinitiated I+V upon MRD conversion was evaluated in the randomized VISION/HO41 phase 2 study. Four-year follow-up including long-term toxicity and MRD kinetics are reported. Patients received ibrutinib for 2 (28-day) cycles followed by 13 cycles of I+V. Patients reaching undetectable MRD at 4 years (<10-4, flow cytometry) in the blood and bone marrow at cycle 15 (C15) were randomized 2:1 between treatment cessation with reinitiated I+V upon detectable MRD2 (dMRD2; sensitivity of ≥10-2 by flow cytometry) and ibrutinib maintenance. MRD4-positive patients at C15 remained on ibrutinib (dMRD4 arm, defined by MRD sensitivity of ≥10-4 by flow cytometry). With a median of 51.7 months, the estimated 4-year overall survival (OS) was 88%, progression free survival (PFS) was 81%; 14% of patients required next-line treatment (NT). For patients randomized to treatment cessation, 40% had reinitiated therapy per protocol because of dMRD2. No difference between treatment cessation, ibrutinib maintenance, or the dMRD4 arm continuing ibrutinib was seen for OS, PFS, or NT in landmark analysis from C15 time of randomization. Lower toxicity was demonstrated for the treatment-cessation arm. MRD-guided cessation and reinitiation of I+V for R/R CLL is feasible, reduces toxicity compared with indefinite BTK inhibitor, while providing comparable PFS rates. This trial was registered at www.clinicaltrials.gov as #NCT03226301.

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Conflict of interest statement

Conflict-of-interest disclosure: C.U.N. reports research funding from Novo Nordisk Foundation (grant NNF16OC0019302) and from the Alfred Benzon Foundation, and research support, consultancy fees, and/or travel grants from AbbVie, Janssen, Roche, CSL Behring, Takeda, Octapharma, Genmab, AstraZeneca, BeiGene, Synamics, MSD, and Lilly, outside this work. J.D. and H.F. received research funding from AbbVie. J.R. reports consultancy fees from AbbVie, Janssen-Cilag, AstraZeneca, and BeiGene, and speakers' bureau participation fees from AbbVie, Janssen-Cilag, and AstraZeneca. H.T.T.T. reports consultancy fees from AbbVie, AstraZeneca, GlaxoSmithKline, and Janssen. A.P.K. reports research funding and consultancy fees from AbbVie and Janssen, and speaker's fee from AbbVie. M.-D.L. reports travel expenses from Janssen, AstraZeneca, and AbbVie, and a research grant from AbbVie. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram. m, months.
Figure 2.
Figure 2.
OS, PFS, and time to NT. Outcome visualized as Kaplan-Meier curves on the intention to treat population (n = 225) for (A): OS, (B) PFS, and (C) time to NT from start of treatment. Landmark analyses for (D) OS, (E) PFS, and (F) NT are presented from time point of randomization at end of cycle 15 for arm A, ibrutinib maintenance; arm B, treatment cessation; and the nonrandomized arm.
Figure 3.
Figure 3.
Reinitiation and dynamics of response per patient. For patients in arm B (treatment cessation), (A) time to reinitiation of treatment per protocol is provided. For those who did not reinitiate treatment, (B) MRD kinetics are provided. Please note that 4 patients met the dMRD2 criteria without reinitiating therapy (see text for details). (C) Dynamics of MRD until reinitiation for the patients reinitiating treatment per protocol, dashed lines indicate the level of dMRD for individual patients at time of reinitiating therapy, whereas (D) provides the MRD kinetics for those patients after reinitiation. Data cutoff for panels B-D is 24 October 2023, MRD results tested every 3 to 4 months. MRD levels are indicated, MRD2 = 1% = 10−2, MRD3 = 0.1% = 10−3, and MRD4 = 0.01% = 10−4.
Figure 4.
Figure 4.
Risk of infection. Risk of infection (CTCAE grade ≥2) from end of cycle 15 for arm A (ibrutinib maintenance), arm B (treatment cessation), and nonrandomized patients continuing ibrutinib. CTCAE, common terminology criteria for AEs.
See this image and copyright information in PMC

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