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Venetoclax Consolidation a Feasible Strategy After BTKi in CLL

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Key Takeaways

  • Venetoclax consolidation therapy post-BTKi treatment shows promise in CLL, achieving high uMRD rates and addressing BTKi-related toxicities.
  • The study involved 20 patients, with 89% achieving uMRD and 92% uMRD in venetoclax monotherapy.
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Switching to venetoclax led to sustained high rates of undetectable minimal residual disease, the investigators found.

Venetoclax (Venclexta; Abbvie, Genentech) consolidation therapy is a feasible strategy for patients with chronic lymphocytic leukemia (CLL) following treatment with Bruton tyrosine kinase inhibitors (BTKi), a new report suggests.

The findings could help clinicians limit some of the toxicities associated with long-term BTKi therapy. The report was published in eJHaem.1

Taken together, the findings suggest that the use of venetoclax following BTKi discontinuation is a feasible strategy that may help overcome toxicity-related challenges associated with long-term BTKi use. | Image credit: jarun011 - stock.adobe.com

Taken together, the findings suggest that the use of venetoclax following BTKi discontinuation is a feasible strategy that may help overcome toxicity-related challenges associated with long-term BTKi use. | Image credit: jarun011 - stock.adobe.com

BTKis have been part of a revolution in the care of CLL, noted corresponding author Benjamin Heyman, MD, of the University of California San Diego Moores Cancer Center, and colleagues. However, they noted that BTKi treatment generally is continuous until disease progression or until side effects become intolerable, and long-term use of these therapies can lead to significant cardiovascular toxicities, most notably atrial fibrillation and hypertension.2

Venetoclax is a BCL-2 inhibitor that has shown significant success in patients with CLL, albeit with a risk of tumor lysis syndrome. Previous research examining the combination of BTKi’s and venetoclax has yielded promising results, offering hope of a time-limited therapeutic option, Heyman and colleagues said.1

“However, there is increased toxicity with combination therapy, which can lead to dose reductions or discontinuation,” the authors said. “Sequential consolidative strategies employing the use of both a BTKi and venetoclax have the potential to overcome these challenges.”

Heyman and colleagues decided to analyze the outcomes of 20 patients with CLL who were treated at a single medical center between the years 2015 and 2024. All of the patients received a BTKi (either ibrutinib [Imbruvica; Pharmacyclics, Johnson & Johnson] or acalabrutinib [Calquence; AstraZeneca] and stopped treatment either due to intolerable side effects or personal preference. None of the 20 patients included in the analysis experienced progression while on a BTKi.

After BTKi discontinuation, the patients received venetoclax either as monotherapy (70%) or in combination with the monoclonal antibody obinutuzumab (Gazyva; 30%). Venetoclax was administered with the standard 5-week ramp-up with a maximum dose of 400 mg daily, the investigators said. Obinutuzumab was administered at the standard dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 6. Therapeutic response was measured using minimal residual disease (MRD), with undetectable MRD (uMRD) defined as <10⁻⁴; low MRD defined as ≥10⁻⁴ through <10⁻², and high MRD defined as ≥10⁻².

The patients in the cohort were on BTKi therapy for a median time of 29.3 months before switching to venetoclax, and 20% of patients reduced their BTKi dose prior to switching. Ninety percent of patients achieved a partial response to BTKi therapy, and the remaining 10% of patients had stable disease, the authors said. Eleven patients had overlap between their time on BTKis and their venetoclax ramp-up. The median time on venetoclax-based therapy was 13 months, the authors said, and as of their reporting, one patient remained on venetoclax-based therapy.

The use of venetoclax-based consolidation therapy proved largely effective, the authors said. Overall, at a median follow-up of 47.4 months, 89% of participants showed a best peripheral blood MRD response of uMRD, 5.5% of participants achieved low MRD, and 5.5% of participants had high MRD following therapy. For patients on venetoclax monotherapy, the uMRD rate was 92%, and for patients on combination venetoclax/obinutuzumab therapy, the uMRD rate was 83%.

Four patients experienced progression after venetoclax-based therapy, the investigators said. Of the 4 patients who had subsequent therapy, half were symptomatic, and the other half received treatment as part of a clinical trial, the authors said. Four patients experienced neutropenia and/or diarrhea leading to reductions in venetoclax dosage. Two patients died, though Heyman and colleagues noted their deaths were unrelated to CLL or their CLL therapy.

Taken together, the investigators said their findings show that the use of venetoclax following BTKi discontinuation is a feasible strategy that appears to yield high rates of uMRD and may help overcome toxicity-related challenges associated with the therapies. Heyman and colleagues said their findings warrant additional study in prospective clinical trials.

References

1. Heyman B, Choi M, Kipps TJ. Venetoclax consolidation after Bruton tyrosine kinase inhibitor treatment for patients with chronic lymphocytic leukemia. EJHaem. Published online June 25, 2025. doi:10.1002/jha2.70085

2. Abdel-Qadir H, Sabrie N, Leong D, et al. Cardiovascular risk associated with ibrutinib use in chronic lymphocytic leukemia: a population-based cohort study. J Clin Oncol. 2021;39(31):3453-3462. doi:10.1200/JCO.21.00693

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