Chronic lymphocytic leukaemia (CLL) research | Cancer Research UK
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Chronic lymphocytic leukaemia (CLL) research

All treatments must be fully researched before they can be adopted as standard treatment for everyone. This is so that we can be sure they work better than the treatments we already use. And so we know that they are safe.

First of all, treatments are developed and tested in laboratories. Only after we know that they are likely to be safe to test are they tested in people, in clinical trials. Cancer Research UK supports a lot of UK laboratory research into cancer and also supports many UK and international clinical trials.

Research into CLL treatment is looking into what causes CLL. It is also looking at treatments with chemotherapy, biological therapies, transplants, and ways of finding remaining leukaemia cells.

 

CR PDF Icon You can view and print the quick guides for all the pages in the Treating CLL section.

 

 

Why we need 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. Cancer Research UK supports a lot of UK laboratory research into cancer.

Tests using patients are called clinical trials. Cancer Research UK supports many UK and international clinical trials.

Our 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 for chronic leukaemia, visit our database of clinical trials. 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.

Here is a video on what it's like to take part in a clinical trial:

View a transcript of the video (Opens in a new window)

 

Finding the causes of CLL

The FAMILIAL CLL study  which is currently on hold, 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). This trial has now closed and we are waiting for the results.

 

Studying CLL cells

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.

 

Antibiotics and CLL symptoms

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. This trial has now closed and we are waiting for the results.

 

Chemotherapy for CLL

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 which has now closed 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 Care 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

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)

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.

The LenD trial is looking at a combination of dexamethasone and lenalidomide for CLL that has got worse or has come back. The aim is to reduce the side effects of treatment by giving a lower dose of lenalidomide.

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. This trial has now closed and we are waiting for the results.

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 trial has now closed and we are waiting for the results.

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. This trial has now closed and we are waiting for the results.

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. 

A trial is comparing ofatumumab to other treatments for CLL that has got worse or has come back, despite having a chemotherapy drug called fludarabine. This trial has now closed and we are waiting for the results.

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.

The COSMIC trial is looking at different doses of ofatumumab in combination with fludarabine and cyclophosphamide chemotherapy for CLL. This trial has now closed and we are waiting for the results.

Ibrutinib

Ibrutinib (Imbruvica) is a type of cancer growth blocker. It stops signals that cancer cells use to divide and grow. The phase 3 RESONATE trial compared ibrutinib with ofatumumab in people with CLL or small lymphocytic lymphoma (SLL) that had come back or was no longer responding to treatment. SLL is when the cancerous lymphocytes are in the lymph nodes rather than the blood.

The trial team found that on average the people who took ibrutinib had a longer time without any sign of their cancer growing again compared to those who had ofatumumab. Doctors call this an improvement in progression free survival. The trial team also found that the average length of time people lived (whether or not their cancer was any worse) was better for those taking ibrutinib. Doctors call this overall survival. They found at 12 months, 9 out of 10 people (90%) were alive in the ibrutinib group compared to around 8 out of 10 people (80%) who had ofatumumab.

The IcICLLe trial is also looking at how well ibrutinib works for CLL. This trial has closed and we are waiting for the results. The IcICLLe extension trial is looking at the combination of ibrutinib and the monoclonal antibody obinutuzumab.

The HELIOS trial is looking at ibrutinib with bendamustine and rituximab for CLL. This trial has now closed and we are waiting for the results.

The FLAIR trial is comparing ibrutinib and rituximab with fludarabine, cyclophosphamide and rituximab for people who haven't yet had treatment for CLL. 

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. This trial has now closed and we are waiting for the results. 

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. This trial has now closed and we are waiting for the results.

Obinutuzumab

This is a new type of monoclonal antibody. It is also known as GA101 and Gazyvaro. Like rituximab, obinutuzumab seeks out the CD20 protein on the surface of CLL cells.

In America, the CLL11 trial found that adding obinituzumab to chlorambucil chemotherapy works better than chlorambucil alone. This was a phase 3 study and the people taking part were older, with an average age of 73, and they also had other health issues.

The Scottish Medicines Consortium (SMC) have said that obinutuzumab should be available as a treatment for people within the NHS in Scotland. They say it should be available for people as a first treatment and who are unable to have fludarabine chemotherapy because of their other health problems. The National Institute for Health and Care Excellence (NICE) say obinutuzumab can be given in combination with chlorambucil for people who have not had previous treatment. It is for people who cannot have fludarabine because of other health problems, or who are not suitable for treatment with bendamustine. 

The GALACTIC trial is looking at whether having obinutuzumab after chemotherapy reduces the risk of CLL coming back.

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.

Duvelisib (IPI-145) is another type of cancer growth blocker. The IPI-145-07 trial is comparing ofatumumab with duvelisib for CLL or small lymphocytic lymphoma (SLL) that has come back or continued to grow despite treatment. The trial team want to find out how well these treatments work for CLL or SLL, to learn more about the side effects of duvelisib, and how both these treatments affect quality of life. This trial has now closed and we are waiting for the results.

The IPI-145-12 trial is for people who have already taken part in the above trial (IPI-145-07). The people taking part will have whichever drug they didn't have when they were in the IPI-145-07 trial. The aims of the study are to see how well the drugs work for CLL or SLL that has continued to grow, and to learn about the side effects of taking one treatment and then the other.

Idelalisib (Zydelig) blocks a protein called PI3K (it is a PI3K inhibitor) and helps stop cancer cell growth. A phase 3 trial compared idelalisib and rituximab with rituximab and a dummy drug (placebo). Over 200 people with CLL that had come back (relapsed) took part in the trial. Most had advanced disease, and they all had other medical conditions which meant they couldn't have standard chemotherapy.

The trial team found that on average the people who had idelalisib and rituximab had a longer time without any sign of their cancer growing again (progression free survival) compared to those who had rituximab and placebo. At 24 weeks, they found that 93 out of 100 people in the idelalisib group (93%) were alive and the cancer had not started to grow again, compared to 46 out of 100 people in the placebo group (46%).

At 12 months, the trial team looked at how many people were alive (whether or not the cancer was any worse). This is called overall survival. They found that 92 out of 100 people in the idelalisib group (92%) were alive compared to 80 out of 100 people having rituximab and placebo (80%). The trial team felt there was no overall increase in the number of side effects for the people having idelalisib. The follow up of these patients was relatively short, and so researchers need to find out if idelalisib is safe in the long term.

The CALiBRe trial is finding out exactly how idelalisib works in people with CLL.

The Scottish Medicines Consortium (SMC) have recommended Idelalisib (Zydelig) for people with CLL living in Scotland. In England and Wales, the National Institute for Health and Care Excellence (NICE) have approved idelalisib for some people with CLL. You may have it if you have not had any treatment yet, and your CLL has certain genetic changes. Or if you have had treatment, but your CLL has come back (relapsed) within 2 years. 

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. This trial has now closed and we are waiting for the results.

You can find information about UK trials for CLL on our database of UK clinical trials.

 

Steroids

A phase 2 trial is looking at a new combination of the drugs to treat types of leukaemia and lymphoma including CLL. The drugs are bezafibrate, which lowers cholesterol in the blood, and medroxyprogesterone, which is a steroid

 

Cyclosporin A

Cyclosporin A can reduce the activity of your immune system and may affect the rate at which leukaemia cells grow. The CyCLLe trial is looking at cyclosporin A (CsA) for CLL. The researchers want to find out if CsA changes the rate at which leukaemia cells grow and how long they live, if CsA helps people with CLL and to learn more about the side effects.

 

Vaccine research

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.

 

Stem cell and bone marrow transplants

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

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. 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.

Half matched stem cell transplants

The UK Haplo study is looking at using donor stem cells from a family member who is at least a 50% match with the person having the stem cell transplant.

In most allogeneic transplants, the donor is someone who is a very close match to the person having the transplant. This is usually a brother or sister. It could also be from a donor who isn't a relative. But doctors can't find a match for about a third of those needing a transplant. An option for these people is a half matched transplant, where the donor is at least 50% match with the person having the transplant. In the past these transplants have been difficult to do. You can react to the donor cells, causing a severe immune response. But researchers think they have found a way to deal with this by using a drug called cyclophosphamide. The aims of the UK Haplo study are to find out how well high dose cyclophosphamide works with a half matched stem cell transplant, how safe it is, and to learn more about the side effects and quality of life for people having this type of transplant.

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.

 

Finding remaining leukaemia cells

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).

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Updated: 26 March 2015