Venetoclax and obinutuzumab

Venetoclax and obinutuzumab is a combination of medicines. It is used to treat some people with chronic lymphocytic leukaemia (CLL).

Venetoclax

Venetoclax is a targeted medicine that helps slow down the progression of CLL. It blocks a protein in CLL cells called BCL-2. This protein stops CLL cells dying when they should. Blocking it makes the cells self-destruct and die.

The brand name for venetoclax is Venclyxto.

Obinutuzumab

Obinutuzumab is an antibody therapy made with antibodies produced in a lab. They are monoclonal antibodies, which means they are all of one type. The antibodies stick to a protein on the surface of CLL cells called CD20. This triggers your immune system to destroy the CLL cells.

The brand name for obinutuzumab is Gazyvaro.

Venetoclax and obinutuzumab is suitable for adults. Your haematology team might recommend it if you have CLL that needs treatment, and you have not had treatment for it before.

Treatment aims to reduce your symptoms and keep your CLL under control for as long as possible with as few side effects as possible.

Before prescribing venetoclax and obinutuzumab, your haematology team will make sure it is suitable for you.

You may have:

• Blood tests to check your blood cell counts
• Blood tests to check your liver and kidney function, and the levels of salts and minerals in your body
• Blood tests to check whether you have an active infection or infections that could flare up during treatment, such as viral hepatitis
• Checks of your heart health
• A CT scan or MRI scan to find out if CLL is affecting your organs, like your spleen

Your team may recommend other tests, depending on your circumstances.

Your haematology team may ask if there is any possibility you might be pregnant. Venetoclax and obinutuzumab is not recommended during pregnancy.

Things to tell your haematology team

Some medicines, supplements and food may affect how well your treatment works. Or they may increase your risk of side effects. It is important to tell your haematology team about any medicines you are taking. This includes prescribed medicines and medicines you have bought yourself without a prescription.

Examples include:

• Herbal medicines such as St John’s Wort.
• Some blood thinners or medicines used to prevent blood clots, like warfarin.
• Some medicines to treat infections, including some antibiotics, antifungal and antiviral medicines.
• Some medicines used to treat high blood pressure or heart problems.
• Some medicines used to prevent or treat stroke, or blood clots in your legs or lungs.
• Some medicines used to lower cholesterol.
• Some medicines used to treat epilepsy.
• Some medicines used to treat a rare sleep problem called narcolepsy.
• Blood pressure medicines. You may need to stop these on the day of each obinutuzumab dose, to reduce the chance of low blood pressure.

Venetoclax and obinutuzumab contain several ingredients. Tell your haematology team if you have any allergies or sensitivities.

• Swallow your tablets whole with a glass of water.
• Do not chew, crush, or break your tablets and do not dissolve them in water.
• Try to take your tablets at about the same time each day. Take them with a meal because this helps your body absorb the right amount of venetoclax.
• You should drink plenty of water to help reduce the side effects of venetoclax. Especially on the days before and the day you start taking it. Also, whenever you increase your dose.
• You need to take medicine to help control your uric acid levels. You’ll start this a few days before you begin your course of venetoclax. You carry on taking it until you are on a stable dose of venetoclax, or longer if needed. Your doctor will prescribe it for you.
• Avoid grapefruit, bitter oranges (Seville oranges) or starfruit (carambola) while taking venetoclax. This includes the fruit, fruit juice, or foods or supplements containing them. These foods affect how much medicine your body absorbs.
• Do not take supplements containing St John’s Wort while taking venetoclax. This is because it affects how much medicine your body absorbs.

If you miss a dose

If you forget to take venetoclax:

• Take it as soon as you remember, if it’s within 8 hours of your dose time.
• If it’s longer than 8 hours by the time you realise you forgot to take your tablet:
  • Skip the missed tablets
  • Take your next tablets at the usual time the following day
• If you are sick (vomit) after you’ve taken your tablets, don’t take any more tablets that day. Take your next dose at the usual time the following day.

The day before having obinutuzumab, you may start medicine to control your uric acid levels. This helps prevent a serious side effect called tumour lysis syndrome. Your doctor will prescribe it for you and tell you when to take it.

• You also need to drink plenty of fluids before you have obinutuzumab. This helps prevent serious side effects.
• About an hour before each dose of obinutuzumab, you’ll have medicine to help prevent any reactions to it. This may include:
  • Paracetamol.
  • Antihistamines, which may make you feel sleepy or drowsy. You should not drive if you feel this way.
  • Steroids (you might only have these during your first two doses).
• You then have obinutuzumab through a thin tube (cannula). This is usually in your arm or the back of your hand. It usually takes around 4 to 5 hours the first time you have the drip.

You start obinutuzumab treatment first. You start with a low dose. You usually start venetoclax 3 weeks after your first dose of obinutuzumab.

You have venetoclax and obinutuzumab treatment in 28-day cycles:

• You have six cycles of venetoclax and obinutuzumab
• You have another six cycles of venetoclax alone

Most people have their dose of venetoclax and obinutuzumab increased over the first two 28-day cycles. Then they have four more cycles of obinutuzumab and venetoclax, followed by six cycles of venetoclax on its own.

Obinutuzumab

You start with a low dose infusion. Your doctor usually increases the dose over the first week until you reach the full dose of 1,000mg. Then you have 1,000mg once a month.

Venetoclax

Venetoclax comes as film-coated tablets containing 10mg, 50mg or 100mg of venetoclax. The number of tablets you need to take should be printed on the medicine packaging. If you are not sure, ask your doctor or nurse.

You take venetoclax once a day, starting on a low dose of 20mg. Your doctor usually increases the dose over 4 weeks until you reach the full dose of 400mg. Your dose is increased slowly to help prevent tumour lysis syndrome. You might hear people call this the ‘ramping up’ stage.

For the first 4 weeks of venetoclax treatment, you’ll get a new pack each week. They usually come as blister packs with the daily dose you need contained within each blister. This will help you take the right dose each day while your doctor is increasing your dose.

You usually have obinutuzumab at a hospital day unit and go home the same day. Some people may need a short hospital stay.

You usually go to a hospital day unit for your first dose of venetoclax, and when your dose is increased. This is so you can be monitored closely. Some people may need a short hospital stay.

The rest of the time, you can take venetoclax at home (or wherever you are staying). You can store venetoclax at room temperature. Keep your tablets safe where children cannot see or reach them.

In the first month, you have four doses of obinutuzumab. After this, you have an obinutuzumab infusion on day 1 of the next 5 cycles.

During the first few weeks of treatment with venetoclax, you should take it in the morning, with food. This will help with follow-up blood tests while your doctor increases your dose.

From cycle 1, day 22 onwards, you also take venetoclax tablets once a day, every day. Try to take your tablets at the same time every day, with food.

Do not stop taking venetoclax without discussing it with your haematology team.

Treatment usually lasts for 1 year. You only have obinutuzumab for the first 6 months of this.

Once you have completed your treatment, you may go on to active monitoring. If you need treatment again in the future, you may be offered the same treatment again if it worked well for you.

Your haematology team may suggest stopping venetoclax and obinutuzumab early and trying a different treatment if:

• It is not working well
• It stops working
• You are having side effects that are difficult to cope with
• Check-ups show it is affecting other parts of your body, like your heart or kidneys
• You become pregnant

During each dose of obinutuzumab, a nurse will regularly check your blood pressure, temperature and oxygen levels.

When you start venetoclax and for each dose increase, you’ll have blood tests:

• Before you take your tablets.
• 6 to 8 hours after taking your tablets. Or more often, if your team think you need it.
• Around 24 hours after taking your tablets. You usually come back to the hospital for this.

The exact timing of your blood tests may vary. It may depend on where you live and how long it takes you to travel to and from the clinic.

Once you are on a stable dose of venetoclax and obinutuzumab, your haematology team will continue to monitor you. This is to check how well your treatment is working and how well your body is coping with it.

• You’ll have regular blood tests to check:
  • Your blood cell counts.
  • How well your liver and kidneys are working.
  • The levels of salts, minerals and uric acid in your body.
• You’ll have regular blood pressure checks.
• Your doctor or nurse will examine you to check for signs of infection, or signs of other side effects.
• You may have other examinations and scans to check the size of your lymph nodes and organs, like your spleen.
• Your team might recommend other tests, depending on your circumstances.

There are some precautions to be aware of when you are taking venetoclax and obinutuzumab.

• Both venetoclax and obinutuzumab can make you vulnerable to infections. You might need to take medicines to prevent infections while you’re having treatment.
• You should avoid eating grapefruit and starfruit (carambola). This includes the fruit, fruit juice, or foods or supplements containing them.
• You should avoid eating bitter oranges (Seville oranges). This includes the fruit, bitter orange juice or food made with bitter oranges, like marmalade.
• Venetoclax may make you very tired or dizzy. This might affect your ability to drive or operate machinery.
• Obinutuzumab can lower your blood pressure. If you are on blood pressure medication, your haematology team may tell you not to take it the day before and the day of obinutuzumab treatment.
• Other medicines might interact with venetoclax and affect how well it works. Your haematology team will tell you whether or how to take other medicines while you’re taking it. Or whether you need a different dose of venetoclax than usual.
• You should not have live vaccines when you have CLL or when you are on venetoclax and obinutuzumab. It is safe to have non-live vaccines. But they might not work as well as they do in other people.

When you’re taking venetoclax and obinutuzumab, you’ll have medicine to help prevent a serious side effect called tumour lysis syndrome. You need to drink plenty of water too, as this will also help prevent it. Try to aim for 1.5 to 2 litres of fluid every day. Especially:

• For 2 days before starting venetoclax
• The day you start venetoclax
• Every time you increase your dose
• Before you have each dose of obinutuzumab

You can include non-alcoholic drinks and non-caffeinated drinks in this amount. But not grapefruit, Seville orange or starfruit juice.

If you're struggling to drink enough, your haematology team might give you fluid through a drip before your treatment.

We do not know what effect venetoclax and obinutuzumab has on pregnancy. Based on animal studies, venetoclax may damage sperm and harm unborn babies. Also based on animal studies, obinutuzumab may cause very low white blood cell counts in babies who were exposed to it during pregnancy.

• If you could get pregnant, it’s important to use effective contraception:
  • While you are taking venetoclax and for at least 30 days after stopping treatment.
  • While you are having obinutuzumab and for 18 months afterwards.
• We do not know whether venetoclax affects the way hormonal contraceptives work. So, you need to use a barrier method like condoms, a diaphragm or cap when you’re on venetoclax and obinutuzumab.
• If you’re on venetoclax and obinutuzumab and you think you might be pregnant, tell your haematology team as soon as possible.
• Venetoclax may cause male infertility. If you are planning to make someone pregnant in the future, tell your haematology team. They will talk to you about options to preserve your fertility, such as freezing your sperm.
• If you have obinutuzumab when you are pregnant, your baby may have a very low white blood cell count at birth and for months afterwards. Your baby should not have any live vaccines until their blood cell count has recovered.

Breastfeeding

We do not know if venetoclax passes into breastmilk or what effect it might have on breastfed babies or children.

Obinutuzumab passes into breastmilk. We do not know how this might affect breastfed babies or children.

You may get some side effects while you are taking venetoclax and obinutuzumab. Some people have very few side effects, whereas others get more serious side effects. They may differ from day to day.

Your haematology team should tell you what side effects to look out for and who to contact if you need to.

This is not a full list of all the side effects that can happen. The patient information leaflets in your medicine packages have more information. Or you can find the leaflets by searching for ‘venetoclax’ and ‘obinutuzumab’ at the Electronic Medicines Compendium.

Here, we list some of the more common side effects of venetoclax and obinutuzumab. These affect at least 10 in every 100 people who take venetoclax and obinutuzumab.

Infections

Contact your team straight away if you think you have an infection. Look out for:

• A high temperature (38°C or higher)
• Shivering, chills or sweating
• Sore throat, sneezing, blocked or runny nose or earache
• Cough, chest pain or shortness of breath
• Burning or stinging when you pee, or peeing more often than usual Tummy problems You might get diarrhoea or constipation. You might feel sick or be sick. If you have these side effects, your team can give you medicines to help.

Fatigue, headache or fever

You might experience extreme tiredness or lack of energy. You might get a headache or fever.

Reaction to the drip

Some people develop a reaction to the obinutuzumab drip. This can sometimes be serious. You may have symptoms like:

• Breathlessness
• Wheezing, coughing or tightness of the chest
• Rapid heart rate, restlessness and confusion

Tell the day unit team immediately if you develop any symptoms while you are having your rituximab drip.

It’s most likely to happen the first time you have obinutuzumab. This is why you have a lower dose at first. You also have your first two doses more slowly than later doses.

Your haematology team will monitor you closely for any signs of a reaction. If needed, they will pause the drip to give you time to recover. They may restart it at a lower rate once you’re feeling better. If it is very severe, or it happens again, you may have to stop obinutuzumab.

There might be some side effects that your haematology team find during regular checks and blood tests. These include:

• Low levels of white blood cells called neutrophils (neutropenia). This can make you more vulnerable to infection.
• Low levels of red blood cells (anaemia).
• Low levels of platelets (thrombocytopenia).
• Changes to the level of salts in your blood, which may be a sign of tumour lysis syndrome.

Venetoclax and obinutuzumab is very good at killing cancer cells. It can cause many cancer cells to break down all at once. When this happens, the dying cells release a lot of chemicals into your blood. This can cause a serious condition called tumour lysis syndrome.

Tumour lysis syndrome affects less than 2 in every 100 people taking venetoclax and obinutuzumab. More than 98 in every 100 people do not get it.

Tumour lysis syndrome can make you very unwell while your body tries to cope with changes to your body salts and levels of uric acid:

• Your kidneys may work less well
• Your heartbeat may become irregular
• You may have seizures (fits)

It can happen to anyone having venetoclax and obinutuzumab to treat CLL. But it’s more likely to happen if you have lots of CLL cells in your body. It’s also more likely if you have other health problems like kidney disease or a swollen spleen. This is because it’s harder for your body to cope with all the chemicals from the dead CLL cells.

Starting obinutuzumab before you start venetoclax helps lower your CLL cell number and your chance of tumour lysis syndrome. You are also closely monitored by your haematology team for tumour lysis syndrome. Most people who get tumour lysis syndrome only have changes on blood tests and do not get symptoms. This is known as ‘chemical tumour lysis syndrome’. However, you still need to know what to look out for, just in case.

Sometimes, venetoclax and obinutuzumab might cause other serious side effects. Most people on venetoclax and obinutuzumab do not get these. But if they do happen, they can be serious, so it’s sensible to know what to look out for.

Sepsis

Sepsis is a severe response to an infection. It is a serious condition and needs

prompt treatment.

Contact your doctor straight away if you get symptoms of sepsis like:

• Confusion, slurred speech or not making sense
• Blue, grey or pale, blotchy skin, lips or tongue (on black or brown skin look on the palms of the hands or soles of the feet)
• A meningitis-like rash, which does not fade when you roll a glass over it
• Breathing difficulties, such as breathlessness or rapid breathing

Heart problems

Obinutuzumab can sometimes cause heart problems. This is more common in people who already have a heart condition. Your team will monitor you for this. Tell them straight away if you have any palpitations, chest pain or breathlessness.

If venetoclax and obinutuzumab is not working well for you, your doctor will discuss your options with you. They might suggest changing your dose, pausing or stopping treatment. They will talk to you about other treatment options that might be suitable.