Follicular lymphoma. What is follicular lymphoma? Freephone helpline

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Follicular lymphoma

Follicular lymphoma is a cancer of the lymphatic system, a type of non-Hodgkin lymphoma. Even though more than 12,000 people are diagnosed with non-Hodgkin lymphoma in the UK every year, many people have never heard of it before.

This leaflet aims to answer the main questions that people diagnosed with follicular lymphoma might ask:

● What is follicular lymphoma? ● What are the symptoms?

● How is it diagnosed and what tests

might I need?

● What does the ‘stage’ mean and

what difference will this make for me?

● What treatments might I be

offered and how would these affect me?

● What is ‘maintenance treatment’? ● What other treatments might I be

offered later on?

What is follicular

lymphoma?

Lymphomas are cancers that develop when lymphocytes (a type of white blood cell) grow out of control.

Lymphocytes usually fight infections and often collect in our lymph nodes (glands), which act like sieves in our lymphatic systems. Lymph nodes are

found in many areas of our bodies: some are easily felt if they are enlarged; others are internal and may only be seen on scans.

When we have an infection such as a sore throat, our bodies make more lymphocytes. These may collect in our lymph nodes, making them swell until the infection has gone. A build-up of cancerous lymphocytes typically makes lymph nodes swell in the same way. Lymphocytes may collect in other places too, such as the spleen, liver, gut, skin and bone marrow. So in some cases of lymphoma, these areas can also be affected.

Groin (inguinal) lymph nodes Neck (cervical) lymph nodes Armpit (axillary) lymph nodes

Lymph vessels _Thymus Diaphragm (muscle that separates the chest from the abdomen) Spleen Liver Figure 1: The lymphatic system

There are two types of lymphocytes, known as B and T lymphocytes (or just B cells and T cells). Most non-Hodgkin lymphomas, including follicular lymphoma, are B-cell lymphomas. Non-Hodgkin lymphoma can also be divided into high-grade (fast-growing) lymphoma and low-grade (slow-growing) lymphoma. Follicular lymphoma is a type of low-grade

lymphoma. This means that the cells in follicular lymphoma generally divide slowly. As a result, the lymphoma develops very gradually, usually over months or even years. Sometimes the cell growth will vary and occasionally enlarged nodes will even shrink again for a while without treatment.

Follicular lymphoma behaves like a chronic (long-term) illness. Many people live with follicular lymphoma for years and have long periods when their health is good. Treatment is not always needed as soon as it has been diagnosed. But from time to time, the illness flares up and causes problems that do need treatment. Recent advances mean that the time between treatments is now much longer, often running into several years.

Who is affected by follicular lymphoma and why?

Follicular lymphoma is the commonest type of low-grade lymphoma. It is more commonly seen in people aged over 50, but it can occur in people of any age.

Lymphomas develop when lymphocytes start to grow out of control or do not die off when they should. This is often due to a change within the genes of the lymphocyte. Although certain gene changes are common in follicular lymphoma, the cause of these remains unknown. It is important that you know:

● You have not done anything to yourself to cause lymphoma. ● You did not inherit it from your parents.

● You did not catch it and you cannot pass it on to others.

What are the symptoms and signs of follicular

lymphoma?

Often people with follicular lymphoma have few symptoms. It is possible you’ll have none at all. But most likely you will have one or more swollen lymph nodes (glands) in your neck, armpit or groin. Usually these are painless and you may simply have noticed a lump by accident. Other symptoms you may have include:

● loss of appetite and weight loss

● unexplained fevers sometimes referred to as ‘B symptoms’ ● drenching sweats, especially at night

● tiredness or fatigue

● unexplained generalised itching ● being more prone to infections.

Sometimes follicular lymphoma will occur in other parts of your body, outside of your lymph nodes, known as ‘extranodal sites’. Various other symptoms are possible if the lymphoma is affecting your internal lymph nodes or organs. These may include shortness of breath or abdominal pain.

If the lymphoma is affecting your bone marrow, it may cause low blood cell counts. This is because the build-up of lymphoma cells in the bone marrow stops new blood cells being produced. The result can be anaemia, causing marked tiredness and shortness of breath, or low platelets, causing unexplained/increased bruising or bleeding.

How is it diagnosed and what further tests may be

performed?

Follicular lymphoma is mostly diagnosed by biopsy of an enlarged lymph node. You may already have had your biopsy, as generally no one will be able to say for sure that you have follicular lymphoma until after this is done. Often a whole node, most often from the neck, armpit or groin, is taken to be examined. In other cases, only a part of the lymph node is removed. The biopsy is examined by a specialist pathologist or more often a team of specialists using a variety of tests.

Other tests that you may undergo will include:

● Blood tests

- to check for anaemia or other low blood cell counts - to check that your kidneys and liver are working well - to give information on how your lymphoma may behave

- for infections such as hepatitis, which could flare up with lymphoma treatments.

● Bone marrow test. This involves a sample taken through a needle inserted into a bone

at the back of your pelvis, just above your hip. The area is numbed with a local anaesthetic but you may still feel some discomfort.

● Scans, which may include:

- Computed tomography (CT) scan, which uses X-rays to produce an image of your internal organs and lymph nodes.

- Magnetic resonance imaging (MRI) scan, which may provide better images of certain parts of the body.

- Positron-emission tomography (PET) scan, a relatively new test that is not often done for follicular lymphoma as its role is not yet completely clear.

- Chest X-ray, which may be useful for monitoring enlarged nodes in the chest or the lungs if they’re affected by lymphoma.

These tests are usually performed when you are an outpatient. It may take a couple of weeks for all the results to be available. It’s normal for you to feel anxious whilst waiting for these tests and the results. But it is very important to have all the information about your lymphoma available to plan the most suitable treatment. Also, because follicular lymphoma is slow

Staging of lymphoma

The ‘stage’ of your lymphoma shows which parts of your body have been affected. This is based on your doctor’s examination and on the results of any tests you have had.

In addition to the numbers, you may also hear ‘A’ or ‘B’ added to the stage. ‘B’ would mean that you have B symptoms, including marked weight loss, severe night sweats and/or unexplained fevers; ‘A’ would mean you have none of these symptoms.

Most people with follicular lymphoma will have stage III or IV disease by the time they are diagnosed. This is because the disease grows so slowly and there may be very few symptoms. Although this is referred to as ‘advanced-stage’ disease, you should not be alarmed. At least 4 out of 5 people with follicular lymphoma will have advanced-stage disease at the time of diagnosis. Lymphoma is not like many other cancers where spread to other areas can be very bad news. This is because effective treatments are available for follicular lymphoma at all stages. These will treat the disease wherever it is.

Grade

You may also hear mention of the ‘grade’ of your lymphoma. This refers to the number of large cells seen under the microscope compared with the number of small cells. Follicular lymphomas are graded as grade 1–2, grade 3a or grade 3b. A lower grade indicates that the lymphoma is likely to grow more slowly than one with a higher grade. The grade of your lymphoma may change over time.

Transformation

Sometimes the lymphoma can become a high-grade lymphoma, where all of the cells are large. This is known as ‘transformation’. Transformed follicular lymphoma and grade 3b follicular lymphoma need to be treated like high-grade lymphoma.

How is early-stage follicular lymphoma treated?

For the small group of people with stage I disease and some people with stage II disease, it is possible that their lymphoma may be cured. Surgery is generally not the best form of treatment as often it will leave behind a few lymphoma cells. These cells start to slowly regrow and in time can spread elsewhere in the body, meaning the lymphoma is likely to return (relapse).

Stage I One group of lymph nodes is affected

Stage II Two or more groups of lymph nodes are affected on one side of the diaphragm (see Figure 1)

Stage III Lymph nodes are affected on both sides of the diaphragm

Instead early-stage follicular lymphoma is usually treated with radiotherapy. Lymphoma cells are readily killed by radiotherapy but the treatment can only be given to small areas, so it is most useful in early-stage lymphoma. Sometimes the radiotherapy may be combined with a short course of chemotherapy or immunotherapy (antibody therapy) too. These treatments are explained in more detail on page 6.

How is radiotherapy given?

Radiotherapy is intensive, focused X-ray treatment, which can effectively treat lymph nodes that are within a small area. The treatment is painless and usually given as 12 short daily sessions, typically lasting 5–20 minutes. Tiredness is a common side effect, due in part for many people to the amount of travelling involved – radiotherapy can only be given at certain specialist hospitals. Your specialist should discuss other potential side effects with you before you start treatment. Further information on radiotherapy is available from our helpline.

How is advanced-stage follicular lymphoma initially

treated?

People with stage III or IV follicular lymphoma, and some people with stage II, are generally considered to have a ‘chronic’ condition. This means it is a condition that they will live with for a long period, which will flare up and need treatment from time to time. With newer treatments, the periods between treatments are becoming longer and people are also living longer overall.

‘Watch and wait’

This may be the first approach recommended for you. Actually it means that you will not be given any active treatment but will instead be ‘watched’ (or ‘actively monitored’) at regular clinic visits. This can be difficult to accept when you’ve just been diagnosed with a type of cancer.

‘Watch and wait’ will be recommended if:

● you are well

● you have no B symptoms

● you have only small lymph nodes that are not causing problems or growing rapidly ● your blood tests are satisfactory

● none of your other organs are affected.

If this applies to you, you won’t have treatment side effects and the treatment can be kept for when your disease really needs it. Your doctors will check you regularly in the clinic and you should let them know between appointments if anything changes, such as new symptoms and lymph nodes growing more quickly or starting to grow in new places. You should try not to be too anxious during this time. Research has shown that you will do just as well if you ‘wait’ for treatment until you really need it. That may be just a few months later or, more commonly, a few years later.

While ‘watch and wait’ is currently the standard approach for patients in this group, one large trial, completed in 2009, looked at whether giving rituximab (see below) on its own rather than traditional chemotherapy was better than the watch-and-wait approach. Doctors are still not sure about this. They need to see if there is any long-term benefit and whether this is worth the risks and inconvenience of having regular treatment.

Treatments

The aim of any treatment in advanced-stage follicular lymphoma is to keep the disease under control for the longest possible time. This is commonly done with chemotherapy (drug treatment) and immunotherapy (antibody treatment). Some types of chemotherapy can be given by mouth (orally); others have to be given into a vein (intravenously). To target as many cells as possible, chemotherapy is generally given as repeated courses, known as ‘cycles’. This is because most treatments kill cells that are dividing, so with each treatment cycle more cells are killed.

Lymphoma that is controlled is said to be ‘in remission’. In a slow-growing lymphoma such as follicular lymphoma, there will always be a few cells not killed by the chemotherapy. Eventually these cells will regrow and the lymphoma will return (relapse). Often remissions will last for a few years but they do tend to become shorter after further courses of treatment.

There are many different types of treatment that can be given when active treatment is required. Which treatment is recommended for you will depend on many factors including:

● how the lymphoma is affecting you now

● how the doctors think your lymphoma is likely to behave ● any other illnesses you have

● your general level of fitness

● your views on the different treatment options available to you.

Combination chemotherapy plus rituximab (eg R-CVP and R-CHOP) When treatment is first required, for many people the recommended treatment will be a combination of chemotherapy and immunotherapy with the antibody rituximab (MabThera®_).

In the UK the regimen most commonly used is either R-CVP or R-CHOP therapy. Combination chemotherapy is often named after the initials of the drugs that are given. CVP consists of two intravenous drugs (cyclophosphamide and vincristine), which are usually given in a day-case unit once every 3 weeks, and prednisolone (steroid) tablets, which are taken orally at home for the next 5 days. CHOP consists of three intravenous drugs (cyclophosphamide, hydroxydaunorubicin [often known as doxorubicin] and vincristine [Oncovin®_{]) and oral prednisolone tablets. Each of these treatments can be combined with}

rituximab, which is also given as an intravenous drip usually on the same day.

Rituximab is an antibody therapy that targets a protein known as CD20. This is present on the surface of normal B lymphocytes and on the cancerous cells of most follicular lymphomas. Rituximab attaches to the CD20 and makes the cell a target for the body’s own immune system. This means other cells of the immune system can destroy the lymphoma. It also makes the lymphoma cells more sensitive to chemotherapy.

Combination regimens have a number of possible side effects (R-CHOP more than R-CVP). You will be given other treatments to help with these side effects known as ‘supportive treatments’. These may include anti-sickness medication, medication to protect your kidneys and treatments to reduce the chances of infection.

The most important side effect of chemotherapy is low white blood cells (sometimes called ‘neutropenia’). This is caused by the chemotherapy damaging the rapidly dividing cells of the bone marrow. Your white blood cells will be at their lowest around 7–10 days after treatment. But, you should always seek immediate advice if you develop signs or symptoms of infection any time after chemotherapy.

Further information about the side effects of chemotherapy, steroids and rituximab and how to deal with them is available from our helpline. Your hospital team will also give you more precise information about what to expect and what to do if certain things happen.

Typically, you will be given 6–8 cycles of treatment. The exact number will depend on how your lymphoma is responding and how well you are coping. You’ll probably have a scan half-way through and another one at the end of treatment. If your bone marrow was affected at the start, your doctors will also want to repeat this test.

These combination treatments have been shown to improve both your chances of going into remission and the time your remission will last. Other combination regimens, such as FC (fludarabine and cyclophosphamide) or FMD (fludarabine, mitoxantrone and dexamethasone), may also be recommended for some people.

Oral chemotherapy (eg chlorambucil)

For many years follicular lymphoma has been treated with the tablet chlorambucil (Leukeran®_{). This is taken at home for 10–14 days in each month, usually for 6 months}

or more. It has relatively few side effects so many people find it easier to cope with than combination intravenous treatment. Prednisolone tablets (steroids) are often given at the same time. For many people, this is enough to control their lymphoma. Although their remission will probably not last as long, when the disease comes back either another course of chlorambucil or a different treatment can be given.

It has recently been agreed by the National Institute for Health and Clinical Excellence (NICE) that doctors can prescribe rituximab along with chlorambucil tablets. This would mean also attending for regular intravenous treatment, which may not be appropriate for everyone.

Less commonly, the drug cyclophosphamide is also given in tablet form. Used on its own, it has a similar effect to chlorambucil. The drug fludarabine may also be given as tablets and on its own. It is stronger treatment than chlorambucil but it also has more chance of causing side effects.

What happens after initial treatment?

Maintenance therapy

Once your lymphoma is in remission after chemotherapy and rituximab, you will probably be offered ongoing treatment with rituximab (known as ‘maintenance therapy’). Trials over the last few years have shown that this can prolong the time until more treatment is required. You will be given rituximab intravenously once every 2–3 months. This can continue for up to 2 years if your lymphoma remains in remission and you’re not getting side effects.

Follow-up

Whether or not you have maintenance rituximab, you will be seen regularly in the outpatient clinic after your chemotherapy has been completed. Initially this will be at least once every 3 months but if all is well your appointments will become less frequent. You should still contact your medical team between appointments if you develop any signs or symptoms of lymphoma.

Most of your follow-up will involve you telling the doctors how you feel and a simple examination for lymph nodes and other signs of lymphoma. You will probably have further tests, such as scans or a bone marrow, only if your doctors suspect that your lymphoma is coming back. Because follicular lymphoma can relapse after long periods of remission, it is unusual to be discharged completely from follow-up.

Treatment at relapse

There are many different treatment options available when follicular lymphoma comes back. Once again your exact treatment will depend on many factors including:

● how well you coped with your previous treatment ● how long your remission has been

● whether you are fit enough to consider more intensive options. Chemotherapy

It is possible to re-use many of the treatments previously mentioned (except R-CHOP). Sometimes it may be better to change to a different treatment as this exposes the lymphoma to new drugs.

Rituximab alone

Rituximab can be given on its own to people who have relapsed more than once or those who have not responded to chemotherapy. It can also be used for people who may not be able to cope with the side effects of chemotherapy.

Stem cell transplantation

This is much more intensive therapy: the side effects can be considerable and often mean spending several weeks in hospital. It is normally only used once someone has relapsed at least once. If you are older or not physically fit, a stem cell transplant is unlikely to be a suitable option for you.

An allogeneic transplant uses cells from a matched donor, usually a sibling. It is the only treatment that has so far been shown to cure advanced follicular lymphoma, but there are major side effects and risks. Increasingly so-called ‘mini-transplants’ are being considered. These involve less treatment before the donor cells are given, which can reduce some of the risks but may still offer the chance of a cure. If this is thought to be an option for you, you should have detailed discussions with a specialist bone marrow transplant doctor. For many people with follicular lymphoma, especially those over 60–65 years of age, this is not a realistic option as the risks are too high.

Autologous transplants are a way of giving a high dose of chemotherapy then using a patient’s own stem cells that have previously been stored to ‘rescue’ the bone marrow. They are safer procedures than allogeneic transplants but still likely to cause major side effects. It has been shown that autologous transplants result in a longer remission time. But, when they are best used and for which patients is still not entirely clear.

Bendamustine

Bendamustine (Levact®_{) is a drug that has shown great promise in a number of trials. It has}

been approved for use in the UK for certain people with low-grade lymphoma. It has greater activity than chlorambucil, to which it’s related. But it has fewer side effects than combination chemotherapy such as R-CHOP. On its own, it is given intravenously on 2 consecutive days every 4 weeks. In the future it may instead be used in combination with rituximab or other chemotherapy drugs.

Radioimmunotherapy

Radioimmunotherapy is radiotherapy treatment that is targeted to the lymphoma cells. This is done by joining a radioactive particle to an antibody that will attach to the lymphoma cells, generally to CD20. The treatment (90_{Y-ibritumomab or Zevalin}®_{) can only be given at a few}

hospitals in the UK that have made the necessary special arrangements. It can be given to you as an outpatient, but there are a few precautions you will need to follow once you’re home. In practice, it is not widely used in NHS hospitals.

New therapies/participation in trials

Other drugs being studied in trials for follicular lymphoma include: other antibody therapies against CD20 (eg ofatumumab) or other proteins (eg epratuzumab); and drugs that affect cancer cells in different ways such as bortezomib (Velcade®_{; already used in mantle cell lymphoma) and}

lenalidomide (Revlimid®_).

You may be invited to take part in a trial (or medical study) either for a new lymphoma

treatment or to determine the best combination or sequence of treatments that are already in use. There are benefits of taking part in trials: you may get a new treatment, although no one can say for sure that this is any better until after the trial. You will also be helping people who have follicular lymphoma in the future. The kind of improvements seen recently in lymphoma treatment can only be made with good clinical trials. Taking part is entirely voluntary and you can always opt to have the standard treatment if you prefer.

Treatment options for follicular lymphoma have improved greatly in the last few years. Although for most people the disease remains incurable, the long-term outlook is improving all the time.

Acknowledgement

We are grateful to Dr Kirit Ardeshna for his assistance in reviewing this article. Dr Ardeshna is consultant haematologist at University College Hospital, London.

Useful sources of further information about follicular lymphoma and lymphoma treatments

Macmillan Cancer Support

89 Albert Embankment London SE1 7UQ

 0808 808 00 00 (Monday–Friday, 9am–8pm)  Order line for booklets 0800 500 800  via website

www.macmillan.org.uk

CancerHelp UK

The patient information section of Cancer Research UK  0808 800 4040 (Monday–Friday, 9am–5pm)

 via website

www.cancerresearchuk.org

Leukaemia and Lymphoma Research

39-40 Eagle Street London WC1R 4TH  020 7405 0101  info@beatingbloodcancers.org.uk www.leukaemialymphomaresearch.or.uk Selected references

The full list of references is available on request. Please contact us via email

(publications@lymphomas.org.uk) or telephone 01296 619409 if you would like a copy. McNamara C, et al. Guidelines on the investigation and management of follicular lymphoma.

British Journal of Haematology, 2012. 156: 446–467.

Schaaf M, et al. High-dose therapy with autologous stem cell transplantation versus

chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database

of Systematic Reviews, 2012 Jan 18. 1: CD007678.

Vidal L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. Journal of the National

Cancer Institute, 2011. 103: 1799–1806.

Tageja N. Bendamustine: Safety and efficacy in the management of indolent non-Hodgkins lymphoma. Clinical Medicine Insights: Oncology, 2011. 5: 145–156.

Schulz H, et al. Chemotherapy plus rituximab versus chemotherapy alone for B-cell

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Produced 16.07.2012

Next revision due 16.07.2014

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