Ibrutinib-Venetoclax in Relapsed CLL: MRD-Guided Approach Balances Efficacy and Safety

For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), continuous therapy with Bruton tyrosine kinase (BTK) inhibitors can extend survival but often carries cumulative toxicity and resistance risks.

The phase 2 VISION/HOVON-141 trial, now reporting more than four years of follow-up, shows that minimal residual disease (MRD)-guided cessation and reinitiation of ibrutinib plus venetoclax (I+V) is feasible and safe and provides durable disease control compared to continuous therapy.

The study enrolled 225 patients across six European countries. After two cycles of ibrutinib monotherapy and 13 cycles of combination I+V, those achieving undetectable MRD at cycle 15 (sensitivity 10⁻⁴) in both peripheral blood and bone marrow were then randomized 1:2 to either continued ibrutinib maintenance (Treatment Arm A) or to treatment cessation with MRD-based I+V reinitiation (Treatment Arm B). Patients without MRD clearance at cycle 15 continued ibrutinib maintenance outside randomization.

At a median follow-up of 51.7 months, four-year progression-free survival (PFS) for the entire cohort was 81 percent, and overall survival (OS) was 88 percent.

Among patients achieving undetectable MRD at cycle 15, PFS and OS in Treatment Arm A was 90 percent and 95 percent, respectively, for these patients on ibrutinib maintenance. And in Treatment Arm B, PFS was 85 percent and OS was 91 percent for these patients who stopped I+V treatment after achieving undetectable MRD.

Patients unable to clear MRD by cycle 15 had less favorable outcomes. In this non-randomized group receiving ibrutinib, four-year PFS was 66 percent and OS was 77 percent, lower than either randomized arm.

After treatment cessation in Treatment Arm B, 40 percent of patients eventually restarted I+V therapy after MRD conversion (defined at ≥10⁻²).

Of these patients, retreatment with 12 additional cycles of I+V restored undetectable MRD in 58 percent, and more than half achieved complete remission.

Toxicity rates were lower in the treatment cessation group compared with cohorts on continuous ibrutinib. By three years post-cycle 15, only 31 percent of patients in Treatment Arm B had developed Grade ≥2 infections, versus 63 percent in Treatment Arm A and 55 percent in nonrandomized patients who continued ibrutinib. Bleeding, atrial fibrillation, and hypertension were reported almost exclusively in those on ongoing ibrutinib.

Keep in mind that the trial was not powered for head-to-head efficacy comparisons between cessation and maintenance. And as only 32 percent of patients were eligible for treatment cessation with undetectable MRD in both blood and bone marrow, the generalizability of these results may be limited.

Context in the CLL Landscape

The VISION/HOVON-141 trial confirms that MRD-guided treatment is a feasible strategy and may represent the future direction of CLL management.

Patients who achieved deep remission and entered Arm B were able to stop therapy, experience meaningful time off treatment, and still maintain durable progression-free and overall survival. Importantly, molecular relapse could be detected early and controlled with retreatment, often before clinical progression occurred.

This approach combines the advantages of fixed-duration therapy—durable remissions, reduced cumulative toxicity, and improved quality of life—with the precision of MRD monitoring. For patients and clinicians, the results validate MRD-guided therapy as an evidence-based alternative to continuous BTK inhibition, balancing efficacy with safety while reshaping long-term treatment goals in relapsed CLL.

Reference
Niemann CU, Dubois J, Nasserinejad K, et al. Long-term follow-up of MRD-guided ibrutinib plus venetoclax in relapsed CLL: phase 2 VISION/HOVON-141 trial. Blood Adv. 2025;9(15):3665-3675. doi:10.1182/bloodadvances.2024015180.