Paper Details

ABSTRACT

Introduction: In contrast to frontline chronic lymphocytic leukemia (CLL), fixed-duration treatment options for relapsed/refractory (R/R) CLL remain limited. Continuous Bruton tyrosine kinase inhibitor (BTKi) therapy is associated with cumulative toxicities, particularly infections, whereas treatment discontinuation raises concerns regarding loss of disease control. Whether MRD-guided discontinuation of BTKi therapy after fixed-duration ibrutinib plus venetoclax (I+V) can preserve long-term progression-free survival while reducing long-term toxicity remains unknown.

Methods: HOVON141/VISION (NCT03226301) is a prospective, randomized, multicenter phase II study in patients with R/R CLL. All patients received 15 cycles of I+V. Patients achieving undetectable MRD (uMRD, <10^-4) in both bone marrow and peripheral blood at cycle 15 were randomized 1:2 to either continuous ibrutinib maintenance (arm A, n=24) or treatment discontinuation with MRD-guided reinitiation upon MRD recurrence or progressive disease (arm B, n=48). Patients not achieving uMRD after I+V continued ibrutinib and comprised a non-randomized cohort (n=153). This final analysis was performed after all patients completed 7 years of follow-up (FU) from registration. All statistical analyses were considered exploratory because the randomized comparison was not powered for formal between-arm comparisons.

Results: In total, 225 patients were included. Median follow-up was 84.4 months. Landmark analyses included the 188 patients who reached the randomization time point: 24 in arm A, 48 in arm B, and 116 in the non-randomized MRD-positive cohort. Median progression-free survival (PFS) was virtually identical between randomized arms (81.4 vs 81.5 months), and 89.7 months in the non-randomized MRD-positive cohort. Median overall survival (OS) was not reached in any group. Estimated 84-months OS rates were 74%, 68%, and 80%, respectively.

Grade ≥3 infections were substantially less frequent following treatment discontinuation than during continuous ibrutinib treatment. In an exploratory Fine-Gray competing-risk analysis, the estimated cumulative incidence was 15% in arm B versus 38% in arm A and 45% in the non-randomized MRD-positive cohort (P=0.006).

In arm B, 28 of 48 patients (58%) remained treatment-free throughout follow-up, whereas 20 (42%) reinitiated treatment. Time to treatment reinitiation (TRT) was measured from randomization to treatment reinitiation. Using death as a competing risk, the cumulative incidence of TRT was 42% at 60 months. Following treatment reinitiation, median progression-free survival was 46.8 months (95% CI, 35.5-not reached), with 55% of patients remaining progression-free at last follow-up, indicating durable efficacy of MRD-guided retreatment. Further reflecting the lower cumulative incidence of grade ≥3 infections after treatment discontinuation, infectious deaths accounted for 13% compared with 33% during continuous ibrutinib treatment. Cardiovascular deaths were numerically less frequent following treatment discontinuation (7% vs 17%), whereas second primary malignancies accounted for a larger proportion of deaths following treatment discontinuation.

In multivariable analysis, mutated IGHV was the only baseline factor independently associated with superior PFS (HR 0.55, 95% CI 0.34-0.89; P=0.016).

Conclusions: After 7 years of follow-up, this final analysis demonstrates that MRD-guided discontinuation and reinitiation after fixed-duration I+V preserved durable disease control while markedly reducing grade ≥3 infections compared with continuous ibrutinib maintenance. Less than half of patients required retreatment, which remained effective and provided durable disease control after treatment reinitiation. These findings support MRD-guided adaptive BTKi therapy as a feasible, effective, and less toxic alternative to continuous BTKi treatment, reducing cumulative BTKi exposure without compromising long-term disease control in patients with R/R CLL.