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Venetoclax Monotherapy for Relapsed / Refractory CLL

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Medically reviewed by Dr. Brian Koffman

The Bottom Line:

Venetoclax monotherapy is effective for treating relapsed / refractory CLL, including in patients previously treated with BTK or PI3K inhibitors.

Who Performed the Research and Where Was it Presented:

Dr. Arnon Kater from the University of Amsterdam and colleagues published their findings in Lancet Oncology in March 2024.


Targeted therapies have greatly improved the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Still, with so many new therapies, we don’t yet know what order they should be given. Venetoclax is a BCL-2 inhibitor that is one of the main targeted therapies used to treat CLL / SLL. Little is known about its efficacy in patients who have already been treated with therapies that target the B-cell receptor pathway (BTK inhibitors, PI3K inhibitors).

Methods and Participants:

The VENICE-1 study was a phase 3, open-label clinical trial of venetoclax monotherapy for patients with relapsed / refractory CLL. Patients were categorized by whether or not they had previously been treated with a B-cell receptor-associated kinase inhibitor (BCRi). BCRIs included BTK inhibitors (e.g., ibrutinib and acalabrutinib) and PI3K inhibitors (e.g., idelalisib). Patients were treated with 400 mg venetoclax once daily for up to two years and then followed for two years after discontinuation. The primary endpoint was a complete remission rate.


  • Between 2016 and 2022, 258 patients with relapsed / refractory CLL were enrolled in the trial.
  • Of these patients, 191 were BCRi-naïve, and 67 had been previously treated with a BCRi.
  • Among patients previously treated with BCRi, 50 had received ibrutinib (75%), 26 had received idelalisib (39%), and two had received acalabrutinib. These numbers include 11 patients who received both ibrutinib and idelalisib.
  • Significant outcomes are summarized in the table below, with a median follow-up of a little over four years.
Overall response rate85%64%
Complete remission rate35%25%
Median duration of response24 months29 months
Median progression-free survival29 months23 months
Five-year estimated survival75%61%
  • Additionally, both groups of patients experienced improvements in self-reported quality-of-life outcomes, which were assessed using three different questionnaires (a general health-related quality-of-life questionnaire, a leukemia-specific questionnaire, and a fatigue-related questionnaire)
  • Of patients who experienced complete remission, 55% had undetectable measurable residual disease (uMRD) in the blood, and 27% had uMRD in the bone marrow.
  • The most common side effects were low white blood cell count (43%), diarrhea (39%), and nausea (27%).
  • The side effect profile was typical of what has already been seen with venetoclax, and no new safety issues were identified.


Venetoclax monotherapy was effective for treating relapsed / refractory CLL, and outcomes for BCRi-naïve patients were generally better than for BCRi-pretreated patients. Even though early use of venetoclax is preferred, most BCRi-pretreated patients still derive some benefit from venetoclax monotherapy.

This is similar to what has been found in a recent analysis of real-world patient data. Researchers looked at patients with relapsed / refractory CLL treated with venetoclax, venetoclax + rituximab, or venetoclax + obinutuzumab and grouped patients by whether or not they had previous BTKi treatment. They found that treatment-free survival was approximately two years for patients with previous BTKi exposure, but this was shorter than for BTKi-naïve patients. So, while venetoclax therapy is more effective when given earlier, it still has efficacy after BTKi exposure.

Links and Resources:

The full article by Dr. Kater and colleagues can be found here: Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial

Take care of yourself first.

Ann Liu, PhD