MRD-Guided Ibrutinib Plus Venetoclax Effective in R/R CLL

Minimal residual disease (MRD)-guided cessation and reinitiation of ibrutinib (Imbruvica; Johnson & Johnson) plus venetoclax (Venclexta; Genentech, Abbvie) is a safe treatment approach for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a new report suggests.1 The study, which was published in Blood Advances, suggests that MRD-guided therapy offers a way to balance the risks of cessation with those of cumulative toxicity.

The combination of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the BCL-2 inhibitor venetoclax has become a transformative therapeutic option for people with relapsed or refractory CLL, the authors noted. It is sometimes combined with CD20-targeting monoclonal antibodies. Yet, it is not curative, and it comes with significant concerns.

“While continuous treatment may lead to cumulative toxicity or resistance, fixed-duration treatment may lead to undertreatment and early relapse,” they wrote.

The combination of ibrutinib and venetoclax has become a transformative therapeutic option for people with relapsed or refractory CLL. | Image Credit: © CLL cells - sovova

One possible solution, the authors wrote, is the use of MRD to guide therapy. Previous research has shown that undetectable MRD following treatment is an independent prognostic indicator of progression-free and overall survival (PFS and OS, respectively) in patients with CLL.2 However, at the time the investigators initiated their trial, there had not been any studies specifically examining response-guided, time-limited use of ibrutinib plus venetoclax in relapsed or refractory CLL.1

In the phase 2 VISION/HOVON141 trial (NCT03226301), a subset of patients had undetectable MRD (sensitivity < 10-4 assessed by flow cytometry; abbreviated as uMRD4) in the bone marrow and peripheral blood after 15 cycles of venetoclax plus ibrutinib.3 Those patients could safely stop therapy, the authors found. The new report expands on those findings with updated 4-year follow-up data.1

A total of 225 patients, treated at 47 sites across 6 European countries, were initially enrolled in the trial. Patients who achieved uMRD4 after 15 cycles (n = 72) were randomized on a 1:2 basis to continue on ibrutinib until toxicity or progression (n = 24) or to stop treatment after the 15th cycle (n = 48). In the cessation cohort, patients were reinitiated on ibrutinib and venetoclax if they met the threshold of detectable MRD (≥ 10-2; abbreviated as dMRD2). Patients who were MRD4 positive (dMRD4) after cycle 15 remained on ibrutinib.

The investigators found that, at a median follow-up of 51.7 months, the estimated 4-year OS rate was 88%, the 4-year PFS rate was 81%, and 14% of participants required another line of therapy. Within the cessation cohort, 40% of participants reinstated therapy due to dMRD2.

However, there was no statistically significant gap between the different cohorts. Within the ibrutinib maintenance arm, the OS was 95%, PFS was 90%, and next-therapy rate was 14%. For those in the cessation arm, the OS was 91%, PFS was 85%, and the next-therapy rate was 12%. Among those who continued on ibrutinib because they did not achieve uMRD4 after 15 weeks, the OS was 86%, PFS was 76%, and next-therapy rate was 19%.

“Importantly, PFS rates were equally high in patients randomized to MRD-guided treatment cessation and reinitiation, emphasizing the potential to reduce treatment exposure and toxicity by MRD-guided treatment in the R/R CLL setting,” the authors wrote.

They concluded that the cessation and reinitiation of ibrutinib plus venetoclax for relapsed or refractory CLL is feasible and results in lower toxicity compared to indefinite therapy with a BTK inhibitor.

“The MRD-guided approach may also allow for improved patient compliance, thus offering an alternative to the high discontinuation rate reported outside clinical trials for continuous BTK inhibitors,” they concluded.

References

1. Niemann CU, Dubois J, Nasserinejad K, et al. Long-term follow-up of MRD-guided treatment of ibrutinib plus venetoclax for relapsed CLL: phase 2 VISION/HO141 trial. Blood Adv. Published online April 18, 2025. doi:10.1182/bloodadvances.2024015180

2. Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia. 2021;35(11):3059-3072. doi:10.1038/s41375-021-01241-1

3. Kater AP, Levin MD, Dubois J, et al. 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. Lancet Oncol. 2022;23(6):818-828. doi:10.1016/S1470-2045(22)00220-0