Venetoclax for CLL: Treatment Options and Patient Outcomes

Venetoclax (Venclexta, AbbVie) is an oral, targeted prescription medicine that is FDA-approved: 

• For the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
• In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia in adults 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy

Venetoclax is a BCL-2 inhibitor. BCL-2 is a protein in the body that facilitates the survival of CLL cells and has been associated with resistance to chemotherapeutics. BCL-2 is highly expressed in CLL. Of note, venetoclax is the only BCL-2 inhibitor approved for any disease by the FDA. 

In addition, venetoclax is a time‐limited therapy. As such, it offers improved quality of life (QoL) associated with reduced time of treatment, hospital visits, and management of side effects. 

Other agents, called Bruton tyrosine kinase (BTK) inhibitors, also are highly effective in patients with CLL. They include ibrutinib, acalabrutinib, and zanubrutinib. Kinases are enzymes that prompt cell activity. Aberrant kinase activity results in altered cellular function and is a potential driver of uncontrolled cell proliferation and cancer. The medicine idelalisib, an inhibitor of a different kinase, is used in combination with rituximab when CLL comes back after prior cancer treatment. 

Venetoclax in Treatment-Naïve Patients

If you have not previously received treatment for your disease (that is, you are “treatment naïve”), the current standard of care is the combination venetoclax + obinutuzumab (Gazyva, Genentech) or continuous BTK inhibitor therapy. 

Obinutuzumab is a monoclonal antibody that targets the CD20 protein on the surface of both abnormal and healthy B lymphocytes. Once locked onto CD20, obinutuzumab encourages the B lymphocyte to disintegrate. The combination therapy helps your body’s immune system find and kill CLL cells. 

In this regimen, venetoclax is designed to be taken for 12 months − which gives you the chance of a treatment-free period thereafter. In a key study that tested this combination, 46% of patients had complete remission, and 35% had partial remission. 

Patient-Reported Outcomes for Venetoclax-Based Therapy

The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) is a commonly used study measure that collects patient input. A 2021 study in elderly unfit patients with CLL who received venetoclax + obinutuzumab used EORTC QLQ-C30 and the MD Anderson Symptom Inventory (MDASI) with CLL module (MDASI-CLL) to assess whether higher treatment efficacy was achieved at the expense of patients' QoL. 

Patient-reported information showed that baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant deterioration (or improvement). Fatigue and insomnia scores showed clinically meaningful improvement. The authors concluded that treatment goals were achieved without compromising patients' functioning and overall QoL. 

In addition, to read an individual patient’s story about her experience with venetoclax + obinutuzumab, see ‘Janice’s CLL Treatment Experience’.

Venetoclax Treatment for Relapsed or Refractory CLL

Even patients with deep responses to therapy will eventually experience relapse or resistance. Single-agent venetoclax can induce overall response rates of 65% or higher in these patients, with a manageable safety profile. Venetoclax monotherapy can have deep and durable responses in patients with relapsed or refractory CLL.

Patient-Reported Outcomes for Venetoclax Monotherapy

A 2021 study examined QoL associated with venetoclax monotherapy in patients with relapsed/refractory CLL. Significant improvement occurred in the global health status (GHS)/QoL subscale of the EORTC QLQ-C30. In addition, clinically meaningful improvements were observed in role functioning, fatigue, and insomnia, suggesting that venetoclax monotherapy has a positive impact on QoL. 

Future Considerations

New research underway includes testing various combinations of agents in patients with previously untreated CLL, such as venetoclax + rituximab, venetoclax + obinutuzumab, venetoclax + ibrutinib, and venetoclax + obinutuzumab + ibrutinib. 

Results of a 2023 study published in the New England Journal of Medicine showed that venetoclax + obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. Simultaneously, the CAPTIVATE trial demonstrated high response and survival rates in patients with CLL receiving venetoclax + ibrutinib, even if their cancer harbored high-risk genetic features associated with poor outcomes. 

In relapsed/refractory CLL, while patients may initially respond to retreatment with venetoclax, eventually resistance develops. In fact, BCL-2 itself mutates so as not to succumb to inhibition. Several companies are working to develop better BCL-2 inhibitors. 

Find ongoing trials with venetoclax and novel Bcl-2 inhibitors with HealthTree’s Clinical Trial Finder. Create a free account below to access:

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Sources:

• Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial (2018)
• A patient guide to venetoclax treatment - by Abbvie (2019)
• Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial (2021)
• CLL Investigators Look to Write the Next Chapter of BCL-2 Inhibition (2023)
• Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience (2023) 
• First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia (2023)
• 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 (2024)