Chronic lymphocytic leukaemia (CLL) research

All potential new treatments have to be fully researched before they can be adopted as standard treatment for everyone. This is so that

• We can be sure they work
• We can be sure they work better than the treatments that are available at the moment
• They are known to be safe

First of all, treatments are developed and tested in laboratories. For safety reasons, experimental treatments must be tested in the laboratory before they can be tried in patients. If a treatment described here is said to be at the laboratory stage of research, it is not ready for patients and is not available either within or outside the NHS.

Tests using patients are called clinical trials. The trials and research section has information about what trials are including information about the 4 phases of clinical trials. If you are interested in taking part in a clinical trial, visit our database of clinical trials. Choose 'leukaemia: chronic leukaemia' from the dropdown menu. If you are interested in a particular trial, print it off and take it to your own specialist. If the trial is suitable for you, your doctor will need to refer you to the research team. The database also has information about closed trials and trial results.

Everything covered here is the subject of ongoing research. Until studies are completed and new effective treatments are found, these experimental treatments cannot be used as standard therapy for chronic leukaemia.

The FAMILIAL CLL study is trying to find out about the causes of chronic lymphocytic leukaemia. It is studying genes that may be important in the development of CLL and asking people with CLL about their family history. The aim of the study is to identify genes that could increase the risk of CLL.

A small study in the North of England is also trying to find out more about the genes that might cause chronic lymphocytic leukaemia (CLL).

There is a study looking at the abnormal white blood cells (lymphocytes) found in the blood of people with diseases like CLL. Scientists are trying to understand how a particular gene helps these abnormal cells to survive. You may be asked to give a blood sample to help with this study. It is unlikely to affect your treatment in any way, but the information from the study could help to find better treatments for people with CLL and other types of cancer in the future.

CLL can develop very slowly and doctors usually only treat it if you have symptoms. We don't know what causes symptoms to develop but researchers think it may be due to infections. Doctors want to find out if stopping people with CLL getting infections could make it take longer for them to develop symptoms. Then people could wait longer to have treatment. The CLEAR trial is giving a short course of antibiotics to people with early CLL to see if it helps to prevent symptoms.

Research is looking into new chemotherapy drugs, or new combinations, in order to improve treatment. Some trials are looking at combining chemotherapy with biological therapies to see if they can control the CLL better than chemotherapy alone.

The ADMIRE trial is looking at treatment for people with newly diagnosed chronic lymphocytic leukaemia. This trial is looking at standard chemotherapy and the biological therapy rituximab, with or without another chemotherapy drug called mitoxantrone. Earlier trials showed that adding mitoxantrone to standard chemotherapy and rituximab might help to lower the number of leukaemia cells that can be left behind after treatment. 

Another new chemotherapy drug researchers have been looking into is bendamustine (Levact). An American trial compared it with chlorambucil as a first treatment for people with advanced CLL. The results of this trial found that it worked better than chlorambucil. The National Institute for health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC) recommend that bendamustine should be available as a first treatment for people within the NHS. It is only for people with Binet stage B or C and who can't have fludarabine chemotherapy. Trials in America and Germany are now looking at combining bendamustine with other chemotherapy and biological therapy drugs.

Biological therapies are treatments that use natural substances from the body, or drugs made from these substances. They can stimulate the body to attack cancer cells or control their growth. There are different types of biological therapy. Those used for trials into CLL include 

• Alemtuzumab (MabCampath)
• Rituximab (Mabthera)
• Ofatumumab (Arzerra)
• Lenalidomide (Revlimid)
• Newer biological therapies

Alemtuzumab (MabCampath)

Monoclonal antibodies are one type of biological therapy and they recognise and stick to particular proteins found on the surface of cancer cells. A monoclonal antibody called alemtuzumab (MabCampath) is currently used to treat people with CLL whose leukaemia has not responded well to chemotherapy.

You usually have alemtuzumab by drip into a vein. You have to stay in hospital as this treatment takes a few days. You can have treatment under the skin as an outpatient and some studies have suggested that it causes fewer side effects than treatment into a vein. The CAM203 trial is looking at whether giving alemtuzumab as an injection just under the skin works as well as giving it through a drip into a vein. The researchers also want to find out more about the side effects of giving alemtuzumab under the skin.

The CLL207 trial is trying to find out whether alemtuzumab can kill off leukaemia cells left behind after chemotherapy treatment. Sometimes, people with CLL have a small number of leukaemia cells left after they have finished their chemotherapy. Doctors call this minimal residual disease. This trial is looking at using alemtuzumab to kill off these cells.

The CLL210 trial is looking at alemtuzumab with another biological therapy called lenalidomide (Revlimid) and the steroid dexamethasone. The people taking part in this trial have high risk CLL, which means the leukaemia cells have a faulty (mutated) or missing gene called p53. The researchers want to find out if this combination of treatment works as induction therapy, to get the leukaemia into remission. They also want to find out if taking lenalidomide in the longer term (maintenance therapy) keeps leukaemia in remission for as long as possible.

Rituximab (Mabthera)

Research has also been looking at another monoclonal antibody for CLL called rituximab (Mabthera). Rituximab works by seeking out a protein called CD20 found on the surface of the CLL cells. 

We know from research that adding rituximab or mitoxantrone to fludarabine and cyclophosphamide chemotherapy is better for treating CLL than the chemotherapy alone. The combination of fludarabine, cyclophosphamde and rituximab is now first line treatment for physically fit people with CLL. A trial called ARCTIC is comparing the drug combinations of

• Cyclophosphamide, fludarabine and rituximab
• Cyclophosphamide, fludarabine, mitoxantrone and low dose rituximab

Ofatumumab (Arzerra)

Another monoclonal antibody researchers are looking into is ofatumumab (Arzerra). This drug targets the CD20 protein. It is licensed in Europe for people whose treatment of fludarabine and alemtuzumab is no longer working. In 2010 the Scottish Medicines Consortium (SMC) and the National Institute for Health and Clinical Excellence (NICE) decided not to recommend it as a treatment for CLL within the NHS. 

There is a trial comparing ofatumumab to other treatments for chronic lymphocytic leukaemia that has got worse or come back despite having a chemotherapy drug called fludarabine. This trial is for people who have enlarged lymph nodes. The trial aims to find out if ofatumumab helps people with CLL that has got worse despite having fludarabine. The researchers are comparing ofatumumab with other treatments doctors can offer.

The RIAltO trial is looking at ofatumumab with chemotherapy for people with CLL who cannot have intensive treatment. The researchers are comparing ofatumumab and bendamustine with ofatumumab and chlorambucil to find out which is the best combination.

Lenalidomide (Revlimid)

Lenalidomide is a type of biological therapy drug used for myeloma. This drug is also called Revlimid or Celgene. It is being used in trials for CLL. Although the details of how lenalidomide works are not known, it is thought that it triggers the immune system to recognise the CLL cells. It has been used for patients who have relapsed or whose disease is difficult to treat (refractory). Lenalidomide has been used on its own and in combination with rituximab. Clinical trials appear to show that lenalidomide works better with rituximab than on its own. 

The CONTINUUM trial is trying to find out if lenalidomide helps to stop CLL coming back after having two previous types of chemotherapy. The lenalidomide for B cell chronic lymphocytic leukaemia trial is looking at lenalidomide for CLL that has come back or stopped responding to treatment. 

Trials are also looking at giving lenalidomide as a first treatment for CLL. The ORIGIN trial is comparing lenalidomide with chlorambucil in people with B cell CLL who are 65 years or older. The main side effect appears to be that lenalidomide affects the bone marrow. Other common side effects include an upset stomach, diarrhoea, tiredness, tingling, numbness and swelling of hands and feet, and joint pain. More serious side effects include shortness of breath and a pounding heart. Lenalidomide can cause birth defects and is not given to pregnant women.

Newer biological therapies

The LUCID trial in the USA is looking at adding a monoclonal antibody called lumiliximab to the R-FC combination (rituximab, fludarabine and cyclophosphamide). Doctors want to find out if adding lumiliximab to the combination makes it work better against the leukaemia. Lumiliximab targets a protein on the cancer cells called CD23. This trial is for people whose CLL has come back after one or 2 courses of treatment, and who have the CD20 and CD23 proteins on their leukaemia cells. 

Some trials with a drug called flavopiridol seem to show that it could help some people with CLL. Flavopiridol is a type of biological therapy called a kinase inhibitor, which is a type of cancer growth blocker. Trials in the USA are using flavopiridol for CLL that has come back after chemotherapy. 

The PICLLE trial is looking at a new drug called olaparib for chronic lymphocytic leukaemia (CLL). Olaparib is a type of biological therapy called a PARP inhibitor. You take it as a tablet. Researchers think that it can help fight cancer by stopping cancer cells from repairing themselves. This trial aims to find the best dose of olaparib to give, and see how well it works. 

In America the CLL11 trial is looking at whether adding a new monoclonal antibody GA101 (Obinutuzumab) to chlorambucil chemotherapy works better than chlorambucil alone. This phase 3 study is using chlorambucil and GA101 as a first treatment for older people with CLL who also have other health issues.

You can find information about UK trials for CLL on our database of UK clinical trials. Choose 'leukaemia: chronic leukaemia' from the dropdown menu.

CLL cells don't generally show up very well to the immune system. If we can find a way to make the cells show up more clearly, then the immune system may attack the leukaemia cells and so help to control the leukaemia. This is vaccine research. There are several different ways of making cancer cells show up more clearly to immune system cells. There has been research into making vaccines

• From a patient's own CLL cells
• Using specialised blood cells called dendritic cells
• By attaching proteins to CLL cells that will help the immune system to find and kill other CLL cells

This is all very early research and so far, most of it has been lab based, rather than with patients. It will be some years (if ever) before any of these vaccines can become available as a standard treatment.

Studies have looked at improving the techniques of bone marrow and stem cell transplants for CLL. This means having intensive chemotherapy, which will kill off all your bone marrow cells. Then, you have bone marrow or stem cells from a donor given through a drip into a vein. Researchers are currently looking at

• Early transplant for high risk CLL
• Mini transplants (reduced intensity transplant)
• Cord blood stem cell transplants

Early transplant for high risk CLL

The CLL5 trial looked into the timing of transplant in CLL. Usually, less intensive treatments are tried first for CLL and transplant may be used later if the disease is not kept under control. The trial looked into using transplant earlier for people who develop the disease at a young age and who have markers indicating that their CLL is at high risk of coming back quickly after treatment. The trial found that using transplant earlier in these patients did not improve the outcome of the treatment.

Mini transplant (reduced intensity transplant)

A new procedure called mini transplant is being investigated for people with leukaemia. Some doctors call this RIC transplant, which stands for reduced intensity conditioning. In this treatment, the chemotherapy doses are not as high as with regular transplants, so the side effects are not as severe. After the chemotherapy, you have bone marrow cells from someone else (a donor). The chemotherapy treatment you've had suppresses your immune system and allows the donor's blood stem cells to start making new blood cells. 

Some people with CLL have a reduced intensity stem cell transplant or bone marrow transplant using cells taken from their brother or sister. This is called a sibling allogeneic transplant. After the transplant people need to take medicines to damp down the immune system (immunosuppressants). This helps to stop the donor cells attacking the patient's cells (GVHD). But it also increases the risk of getting an infection.

The ProT4 trial is looking at giving extra T cells, a type of white blood cell after a mini transplant. Doctors hope that giving specific T cells called CD4 cells may help boost immunity and reduce the risk of infection. In this trial they are giving extra CD4 cells from the donor a few months after the transplant. This is called a donor lymphocyte infusion (DLI). The doctors also hope that the CD4 cells will recognise and kill any leukaemia cells left behind – something called the graft versus leukaemia (GvL) effect.

Cord blood stem cell transplants

The RIC UCBT trial is looking at using stem cells collected from the umbilical cords of newborn babies. The cells are given to people after a mini transplant (reduced intensity conditioning). These transplants are for people who don't have a relative who can be their stem cell donor. Doctors hope that the umbilical cord stem cells will cause fewer side effects than adult stem cells. 

You can find out about these and other trials for CLL on our clinical trials database. Choose 'leukaemia: chronic leukaemia' from the dropdown menu.

One problem with treating leukaemia is that very small numbers of leukaemia cells can be left behind, even if you seem to have been successfully treated. The numbers are so small that the usual blood and bone marrow tests cannot pick them up. Doctors call this minimal residual disease (MRD). Some studies are looking at new ways of detecting whether there are leukaemia cells left behind after the leukaemia appears to have gone (remission).

One way of doing this is by using a test called the polymerase chain reaction (PCR). PCR looks for genetic changes in cells. This test can find one leukaemia cell among a million normal cells. PCR can help doctors to find out how effective your chemotherapy has been in killing off all your chronic leukaemia cells. This test can help to tell the doctor how quickly your leukaemia is likely to come back (relapse).