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March 5, 2024
Clinical Relevance: Venetoclax can offer your CLL patients a powerful, targeted treatment that is personalized and more effective care with fewer side effects than many other options.
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Oncologists treating chronic lymphocytic leukemia (CLL) and select small lymphocytic lymphomas should strongly consider adding Venetoclax (Venclexta) to their arsenal, given its proven capacity to significantly enhance patient survival.
This imperative is backed by robust studies showcasing Venetoclax’s targeted attack on the B-cell lymphoma 2 (BCL-2) protein, leading to a substantial increase in CLL cell death. Since receiving FDA approval in 2016 for CLL and broadening its application in 2018 for previously treated patients, Venetoclax has set a new standard by outperforming its predecessor, navitoclax, tenfold.
“We see that when we treat a CLL with this drug, we can pretty much trigger the death of CLL cells almost overnight,” Dr. Michael Choi, a hematologist, researcher, and associate clinical professor at the University of California, San Diego tells SurvivorNet.
This landmark development is a strong consideration for reassessment of prevailing treatment regimens, offering oncologists a powerful tool to elevate care and outcomes for their CLL patients including those without a specific genetic mutation (17p deletion) that was previously required for its use..
Related: Understanding PI3K Inhibitors
Mechanism of action
Venetoclax exploits the dependency of cancer cells on the BCL-2 protein for survival.
BCL-2 protein plays a crucial role in cell survival by inhibiting apoptosis, the natural process of programmed cell death, which is essential for the removal of unwanted cells.
In many cancers, including CLL, overexpression of the BCL-2 protein contributes to the survival, proliferation, and accumulation of malignant cells by preventing their apoptosis.
Venetoclax binds directly to the BCL-2 protein, thereby neutralizing its function. This binding disrupts the balance between pro-apoptotic and anti-apoptotic signals within the cell, leading to the initiation of apoptosis in cancer cells that are dependent on BCL-2.
A key aspect to the drug’s success: venetoclax’s action is selective. It primarily targets cancer cells with high levels of BCL-2 expression with minimal impact on normal cells that have no survival reliance on BCL-2.
This selectivity helps to reduce the collateral damage to healthy cells – a common drawback of traditional chemotherapy treatments.
Furthermore, venetoclax results in the displacement of pro-apoptotic proteins (such as BIM) from the BCL-2 protein, thereby freeing these proteins to trigger the apoptosis pathway.
The effectiveness of venetoclax is enhanced when used in combination with other therapeutic agents that further stress cancer cells, leading to synergistic effects that induce cancer cell death.
Indications
Venetoclax is approved for treating CLL, regardless of specific genetic mutations. It can be used on its own or with other drugs.
Patients take venetoclax orally, once daily, with food and water. Dosage is tailored based on the patient’s type and stage of cancer, along with other health considerations.
Dr. Choi emphasizes the importance of a customized treatment plan to improve patient outcomes.
“I think we want to partner with our patients and, and decide together what the best thing for you will be,” he explains. “And sometimes it’s based on tests that they’ve run, maybe certain factors about the CLL cells or genetic changes, but other times it’s really oftentimes centered on your preferences.”
Commonly combined medications with venetoclax include:
- Ibrutinib (Imbruvica): This combination boosts the immune system’s response to slow down CLL growth. Ibrutinib, a BTK inhibitor, is used for CLL treatment after a relapse or in cases with specific resistant genetic mutations. Together with venetoclax, Ibrutinib might offer a stronger strategy for managing the disease and possibly lowering relapse risks. “So we’ll see in the future if those become yet another excellent treatment option for our patients,” Dr. Choi says.
- Obinutuzumab (Gazyvaro): Combining venetoclax with obinutuzumab targets cancer cells in multiple ways. venetoclax blocks the BCL-2 protein, while Obinutuzumab is an antibody targeting CD20 on B cells, including cancer cells. This combination can more effectively fight cancer, potentially with fewer side effects. “We’re seeing some promising signs from that,” Dr. Choi mentions.
- Rituximab (RITUXAN): venetoclax is also used with rituximab, an antibody that helps the immune system identify and destroy B cells, including those that are cancerous.
Related: CAR T Clinical Trials Show Promise
Evidence of Benefit
CLL patients who have a genetic mutation called 17p deletion, or who have received at least one prior therapy tend to get the best results on venetoclax.
Dr. Choi has authored numerous papers looking at the results for venetoclax either alone or in combination with other drugs.
Among the findings he and other researchers have noted:
- The VENICE study: Compared two treatments for people with CLL who had been treated with other drugs before. It concluded that both treatment modalities—venetoclax alone and in combination with rituximab—provided equally effective results for CLL patients.
- The MURANO study: In a pivotal phase III study, venetoclax plus rituximab (Ven-R) demonstrated superior efficacy over Bendamustine plus rituximab (BR) in relapsed or refractory CLL, achieving a 2-year PFS rate of 84.9% versus BR’s 36.3%. The hazard ratio for progression or death was 0.17 (95% CI: 0.11 to 0.25; P<0.001). Ven-R’s benefits were consistent across all subgroups, including those with chromosome 17p deletion. Notably, Ven-R had higher rates of grade 3 or 4 neutropenia but fewer instances of febrile neutropenia and infections, marking it as a significant advancement in CLL management.
- The CLL14 study: The comparison between venetoclax plus obinutuzumab and Chlorambucil plus obinutuzumab demonstrated a 24.1% improvement in PFS and a 41.1% increase in complete response rates (CRR), indicating enhanced efficacy in prolonging the duration without disease progression and achieving remission in CLL patients.
- The CAPTIVATE study: This trial evaluated ibrutinib plus venetoclax in previously untreated CLL patients ≤70 years, showing a CR rate of 56% in those without del (17p), and an overall CR rate of 55%. uMRD rates reached 77% in peripheral blood and 60% in bone marrow, with 24-month PFS and OS rates at 95% and 98%, respectively. Notable grade ≥3 adverse events were neutropenia (33%) and hypertension (6%), highlighting this regimen as a potent, fixed-duration treatment for CLL, offering deep and durable responses across risk groups.
Related: Clinical Trials For CLL
Side effects and contraindications
“Most people don’t experience much as far as side effects,” Dr. Choi says.
However, like any drug, venetoclax can carry side effects which include:
- Low levels of white blood cells
- Diarrhea
- Nausea
- Anemia
- Infections
- Fatigue
Venetoclax can also cause tumor lysis syndrome (TLS), which results from the fast breakdown of cancer cells. TLS can lead to kidney failure, seizures, and death.
To prevent TLS, patients need to drink plenty of fluids, take other medicines, and have regular blood tests.
Venetoclax doesn’t have many effects on the cardiovascular system like many other CLL drugs do. It also doesn’t lead to other common cancer treatment side effects such as hair loss.
Patients on venetoclax should avoid certain medicines, including strong CYP3A inhibitors. Taking them with venetoclax can increase side effects.
Patients also need to avoid citrus including grapefruit, Seville oranges, and Starfruit as these can change the way the body processes the drug.
Venetoclax is not safe for pregnant or breastfeeding women. It may harm the unborn or nursing baby.
Women of childbearing age should use contraception while taking venetoclax and for some time after the last dose to avoid issues.
Patients taking venetoclax should be closely monitored for any symptoms.