Venetoclax Consolidation Is Well Tolerated in Patients with Previously Untreated CLL

Venetoclax (Venclexta) consolidation after 12-cycles of treatment increases the duration of known toxicities and does not prevent the loss of minimal residual disease (MRD) response and subsequent risk of disease relapse in patients with previously untreated chronic lymphocytic leukemia (CLL).

The data comes from the primary analysis of a phase 2 trial (HOVON 139/GiVe, NTR6043) which examined the activity and safety of 12 cycles of venetoclax consolidation after a patient unfit for fludarabine-based treatment was given fixed-duration venetoclax plus obinutuzumab (Gazyvaro). The study also aimed to see whether this could be guided by MRD status.

Enrollment was open to patients aged 18 years or older with previously untreated CLL who had an ECOG performance status of 0–2, and were unfit for fludarabine-based treatment.

The open-label, multicenter, randomized trial enrolled a total of 70 patients who received two debulking cycles of obinutuzumab given intravenously (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle 2), which was then followed by fixed-duration venetoclax plus obinutuzumab for a total of 12 cycles. This consisted of 6 cycles of obinutuzumab given intravenously at 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up followed by 400 mg given once a day daily until completion of cycle 12.

After, patients were randomly assigned 1:1 by MRD status in peripheral blood and given either 12 cycles of venetoclax consolidation irrespective of MRD or venetoclax consolidation if MRD was detected at randomization.

The primary end points of the study consisted of undetectable MRD in the bone marrow and no progressive disease 3 months post the end of consolidation treatment by intention-to-treat with safety assessed in all patients who received at least 1 dose of any drug used in the study. The analysis of the primary end point of this trial is currently ongoing and registered with EudraCT (2015-004985-27).

Of the 70 patients enrolled, a total of 67 (47 men and 20 women) received fixed-duration treatment with 62 of these participants randomly assigned to receive 12 cycles of venetoclax consolidation (n = 32) or MRD-guided venetoclax consolidation (n = 30). One participant assigned to MRD-guided consolidation was MRD positive at the time of randomization.

At a median follow-up of 35.2 months (range, 31.5 to 41.3 months), 16 of the 32 patients in the consolidation group (50% [95% CI 32–68]) and 16 of the 30 in the MRD-guided consolidation group (53% [34–72]) met the primary end point of undetectable MRD in bone marrow as well as no progressive disease.

Of the 32 patients in the venetoclax consolidation group, 22 (69%) reported grade 2-4 adverse events (AEs) compared to 11 (37%) of 30 patients in the MRD-guided consolidation group. Infections mainly made up the AEs seen in these patients with the most common grade 3 or worse AEs consisting of infection 6% in the consolidation group (n = 2) and 3% in the MRD-guided consolidation group (n = 1). Additionally, neutropenia was reported within 6% (n = 2) in the consolidation group and 7% (n = 2) in the MRD-guided consolidation group. No treatment-related deaths were reported within the trial.

The findings demonstrated that both maintenance treatments, fixed duration venetoclax, and MRD-guided venetoclax, were well tolerated and demonstrated high efficacy after the given cycles. MRD-guided venetoclax maintenance treatment also demonstrated low rates of adverse events compared with fixed duration venetoclax. Further research is needed in order to investigate the effectiveness of fixed duration and MRD-guided venetoclax maintenance treatment after venetoclax plus obinutuzumab induction.

_REFERENCES:

_{Kersting S, Dubois J, Nasserinejad K, et al. Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomized, parallel-group, phase 2 trial. Lancet Haematol. 2022;9(3):e190-e199. doi:10.1016/S2352-3026(22)00034-5}