Venetoclax Consolidation After BTKi Shows Promise in CLL

Venetoclax (Venclexta) consolidation after Bruton tyrosine kinase inhibitor (BTKi) therapy discontinuation is a feasible strategy for patients with chronic lymphocytic leukemia (CLL), according to a single-institution retrospective analysis.

Overall, the review included 20 patients who received single-agent venetoclax (n = 14) or venetoclax plus obinutuzumab (n = 6) after discontinuing BTKi (ibrutinib [Imbruvica] or acalabrutinib [Calquence]) due to intolerance or patient preference. Patients were not included if they had disease progression on BTKi.

Of these patients, 19 were evaluable for peripheral minimal residual disease (MRD). At a median of 13.1 months (range, 0.2-63.2) of receiving venetoclax-based treatment, 89% (n = 17) of the evaluable patients had undetectable MRD (uMRD), 5.5% had low MRD, and 5.5% had high MRD. Evaluable patients receiving venetoclax monotherapy (n = 13) had a uMRD rate of 92% and a high MRD rate of 8%. Patients receiving the venetoclax-based combination had a uMRD rate of 83% and a low MRD rate of 17%. The median progression-free survival and time-to-next treatment had not yet been reached at the median follow-up of 47.4 months.

One patient was still receiving venetoclax at the time of the data cutoff. Four patients had disease progression following their consolidation regimen and 4 needed subsequent treatment. There were 2 patient deaths, although neither was related to CLL or the study treatment. Venetoclax dose reductions were required by 4 patients, with all reductions being secondary to neutropenia and diarrhea.

“Initial administration of BTKi can sufficiently treat patients with CLL to bring their disease state to a low tumor bulk, which allows for the addition of sequential venetoclax administration to establish a deep remission,” Benjamin Heyman, MD, a hematologist in the Department of Medicine, Division of Regenerative Medicine, UC San Diego Moores Cancer Center, UC San Diego, San Diego, California, and colleagues wrote in their manuscript.

Study Background

As background for their research, Heyman et al explained in their article that BTKi treatment requires continuous use until progressive disease or intolerable toxicity. Long-term follow-up of covalent BTKi treatment has raised concerns about cardiovascular toxicity—particularly atrial fibrillation and hypertension—which increase over time. Prolonged treatment also heightens the risk of resistance mutations, potentially blocking BTKi efficacy in CLL.

Based on this information, Heyman and colleagues concluded that, “Time-limited therapies that effectively employ BTKi are required to prevent long-term side effects and resistance.”

Accordingly, they launched their retrospective study to examine the potential of sequencing venetoclax consolidation following BTKi treatment.

Patient Characteristics

Among the 20 patients in the retrospective review, the median age was 64 years, with a range of 41 to 82 years. The cohort included 15 men and 5 women. At the time that BTKi therapy was initiated, Rai staging system classification was as follows: stage I in 20% of patients, stage II in 50%, stage III in 5%, and stage IV in 25%. Three-fourths (75%) of patients had received prior treatment, with a median of 1 (range, 0-5) prior therapy. One patient had been previously treated with venetoclax.

BTKi therapy consisted of ibrutinib in 80% of patients and acalabrutinib in 20%. Discontinuation of BTKi was due to atrial fibrillation (25%), preference for fixed-duration therapy (24%), diarrhea (15%), completion of planned therapy (15%), infection (10%), arthralgia (5%), and hemorrhage (5%).

The median number of months of BTKi treatment was 29.3 (range, 1.3-70.3). Response to BTKi showed that 18 patients (90%) achieved a partial response and 2 patients (10%) had stable disease.

Next Steps

“Our data supports that a consolidation strategy for these patients would be feasible to transition them to a time-limited therapy…. Our analysis demonstrates that sequential venetoclax after BTKi is a feasible and effective treatment strategy for patients with CLL that deserves further evaluation in prospective clinical trials,” wrote Heyman et al.

REFERENCE:

Heyman B, Choi M, Kipps TJ. Venetoclax Consolidation After Bruton Tyrosine Kinase Inhibitor Treatment for Patients With Chronic Lymphocytic Leukemia. EJHaem. 2025 Jun 25;6(4):e70085.