MRD-guided ibrutinib plus venetoclax is effective in the treatment of R/R CLL

A new report demonstrates minimal residual disease (MRD)-guided discontinuation and restarting of ibrutinib/ibrutinib (Ibrutinib plus span>Venetoclax (venetoclax) is a safe treatment for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). This study demonstrates that MRD-guided treatment offers a way to balance the risk of discontinuation with the risk of cumulative toxicity.

The combination of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the BCL-2 inhibitor venetoclax has emerged as a transformative treatment option for patients with relapsed or refractory CLL. It is sometimes used in combination with a monoclonal antibody that targets CD20. However, it is not curative, and it raises significant concerns. While continued treatment may lead to cumulative toxicity or resistance, fixed duration treatment may result in undertreatment and early relapse.

One possible solution is to useMRD to guide treatment. Previous studies have shown that undetectable MRD after treatment is an independent prognostic indicator of progression-free survival and overall survival (PFS and OS, respectively) in patients with CLL. However, when the researchers began the trial, there were no studies specifically examining the response-oriented, time-limited use of ibrutinib and venetoclax in relapsed or refractory CLL.

In the Phase 2 trial of VISION/HOVON141 (NCT03226301), a subset of patients developed undetectable MRD in bone marrow and peripheral blood (sensitivity <10-4 as assessed by flow cytometry; abbreviated uMRD4) after 15 cycles of venetoclax plus ibrutinib. These patients can safely discontinue treatment. The new report expands on these findings with updated 4-year follow-up data.

A total of225 patients treated at 47 sites in six European countries were initially enrolled in the trial. Patients who achieved uMRD4 after 15 cycles (n=72) were randomized in a 1:2 ratio to continue taking ibrutinib until toxicity or progression (n=24) or to discontinue treatment after cycle 15 (n=48). In the discontinuation cohort, ibrutinib and venetoclax were restarted if patients reached a detectable MRD threshold (≥10-2; abbreviated dMRD2). No.Patients who were MRD4 positive (dMRD4) continued taking ibrutinib after 15 cycles.

The researchers found that over 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 treatment. Within the cohort, 40% of participants resumed treatment due to dMRD2.

However, there were no statistically significant differences between cohorts. In the ibrutinib maintenance group, OS was 95%, PFS was 90%, and the next treatment rate was 14%. For the discontinuation group, OS was 91%, PFS was 85%, and the next treatment rate was 12%. Among patients who continued ibrutinib because they did not reach uMRD4 after 15 weeks, OS was 86%, PFS was 76%, and the next treatment rate was 19%.

Importantly, PFS rates were equally high in patients randomized toMRD-guided therapy discontinuation and restart, highlighting the potential of MRD-guided therapy to reduce treatment exposure and toxicity in the setting of R/R CLL. Discontinuing and restarting ibrutinib plus venetoclax in relapsed or refractory CLL is feasible and less toxic than indefinite treatment with BTK inhibitors.

An MRD-guided approach may also improve patient compliance, providing an alternative to the high discontinuation rates reported outside clinical trials of sequential BTK inhibitors.

Reference materials:https://www.ajmc.com/view/mrd-guided-ibrutinib-plus-venetoclax-effective-in-r-r-cll