On this page we will discuss BCL-2 inhibitors in the treatment of lymphoma and chronic lymphocytic leukaemia (CLL).
What is the role of BCL-2?
BCL-2 (B-cell lymphoma 2) is one of a family of genes that regulates cell death, called apoptosis. The BCL-2 either inhibits or stops cell death (anti-apoptotic) or induces apoptosis (starting cell death). BCL-2 helps cell growth by blocking programmed cell death by promoting cell survival. Some types of lymphoma and particularly CLL are dependent on BCL-2 for their survival. The expression of this gene is strongly associated with resistance to chemotherapy.
What are BCL-2 inhibitors?
All normal cells undergo programmed cell death. All cells live for a amount of time and then they die at a controlled rate. In some lymphomas, particularly CLL the BCL-2 gene allows them to survive. BCL-2 inhibitors are a targeted therapy that inhibits or stops this gene and that makes lymphoma cells die.
Venetoclax (Venclexta)
Prof John Seymour
Peter MacCallum Cancer Centre & Royal Melbourne Hospital
All normal cells undergo this process as part of the natural cell cycle process. This is where cells grow and die in an orderly way. In some cancers, it has been found that they are able to ‘turn off’ this process and cells grow uncontrollably. CLL is particularly dependent on BCL-2 to survive, as it prevents programmed cell death.
BCL-2 prevents CLL cells from dying. Because these cells do not die and continue to be made in the bone marrow, they begin to crowd out the blood, bone marrow and organs. The protein also protects the malignant CLL cells from chemotherapy, making them resistant to treatment.
Venetoclax is a targeted therapy that can make lymphoma cells undergo apoptosis (programmed cell death). This makes Venetoclax an attractive treatment for CLL.
Venetoclax switches off the BCL-2 protein or the survival signals that keep these cancerous cells alive when they should have died. Venetoclax allows the CLL cells to die naturally.
Indications of use
Prof John Seymour
Peter MacCallum Cancer Centre & Royal Melbourne Hospital
- VENCLEXTA in combination with Obinutuzumab is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) who are considered unfit or unsuitable for chemo-immunotherapy.
- VENCLEXTA in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.
- VENCLEXTA monotherapy is indicated for the treatment of patients with relapsed or refractory CLL with 17p deletion, or patients with relapsed or refractory CLL for whom there are no other suitable treatment options.
There are many trials that are currently available in Australia and internationally. The trials are looking at using Venetoclax in other lymphoma subtypes and in different combinations.
Administration
- Venetoclax is an oral tablet that you take every day
- You start at a low dose and the dose is gradually increased over the first 5 weeks of treatment.
- Patients should be instructed to take
- VENCLEXTA tablets with a meal and water at approximately the same time each day.
- VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.
- Remember to stay hydrated while taking Venetoclax- 6 to 8 glasses of water a day. Plenty of water will reduce side effects
- If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the patient should be instructed to take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose but resume the usual dosing schedule the next day.
Killing too many cells at once can cause a serious side effect called ‘tumour lysis syndrome’, as your kidneys can struggle to remove the high levels of waste products from dying cells.
VENCLEXTA can cause rapid tumour reduction and thus poses a risk for TLS in the initial 5-week ramp-up phase.
Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.
Possible side effects
- Diarrhoea and constipation
- Neutropenia
- Anaemia
- Nausea and vomiting
- Decreased appetite
- Headache
- Tiredness
- Unusual weakness or lack of energy
- Upper respiratory tract infection
- Tumour lysis syndrome (TLS)
Certain drugs and foods can increase your risk of side effects during treatment with Venetoclax.
- Drugs that affect an enzyme called CYP3A4. It is important that your doctor knows about all the medications you are taking as there is a range of drugs that can have this effect, including some antibiotics and herbal remedies such as St John’s Wort (used for depression and anxiety).
- Do not drink grapefruit juice or eat grapefruit or Seville oranges (used in some types of marmalade). These can increase the amounts of Venetoclax in your blood.
