Non Hodgkin's lymphoma research

All 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 ethical and 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 in patients are called clinical trials. The trials and research section has information about what trials are including information about the 4 phases of trials. If you are interested in taking part in a clinical trial, visit our searchable database of clinical trials and pick 'non Hodgkin's lymphoma' from the dropdown menu. If there is a trial you are interested in, print it off and take it to your own specialist. If the trial is suitable for you, your doctor can refer you to the research team.

All the new approaches covered here are the subject of ongoing research. Until studies are completed and new effective treatments are found, these treatments cannot be used as standard therapy for non Hodgkin's lymphoma.

A study is looking at a new type of scan called magnetic resonance spectroscopy (MRS) to see if it can help to predict which type of treatment will work best for individual patients. MRS gives information about the activity inside a cancer, by looking at chemical changes. Researchers want to collect information from the scans and create a database so that they can see how patients' individual biological differences affect how well particular treatments work for them. Doctors hope they will be able to use this information in the future to choose the most appropriate treatment for patients. There is more information about this trial on our clinical trials database. Pick 'lymphoma' from the dropdown menu of cancer types.

The IELSG 26 study is looking at tissue samples and PET scans to try to find the best type of treatment for a type of non Hodgkin's lymphoma called primary mediastinal diffuse large B cell lymphoma (PMBL). PMBL is a very rare type of lymphoma that starts in the glands (lymph nodes) in the centre of the chest (the mediastinum). The study is trying to find out whether PET scans can show how well treatment has worked. The study is now closed and we are waiting for the results. 

A lot of research is looking at new chemotherapy regimes for some types of NHL. Other trials are looking at new ways of giving standard chemotherapy drugs. Drugs and combinations being used include

• CHOP
• R-GCVP
• R-CODOX-M/IVAC
• R-CHOP-B
• Chemotherapy for rare lymphomas
• New types of chemotherapy

CHOP

CHOP chemotherapy has been the standard treatment for high grade NHL for over 10 years now. A number of clinical trials are looking at using different combinations of chemotherapy drugs. Some trials combine CHOP with biological therapies such as rituximab or Zevalin. If you would like to find NHL clinical trials, go to our clinical trials database and and pick 'lymphoma' from the dropdown menu.

R-CHOP, which is CHOP chemotherapy together with rituximab, is recommended by the National Institute for Health and Clinical Excellence (NICE) as the treatment of choice for high grade diffuse large B cell lymphoma. Trials are taking place to find out how effective this combination is in treating different types and stages of non Hodgkin’s lymphomas. So far many of these trials show promising results.

Researchers from Germany have looked at whether having CHOP chemotherapy over two weeks works better than the usual 3 week cycle. They studied patients with high grade NHL. The patients were either aged over 60 or under 60 with disease that had a good prognosis. So far results have been promising. A trial called R-CHOP 14 vs R-CHOP 21 in the UK is comparing CHOP and rituximab every 2 weeks (R-CHOP 14)  with CHOP and rituximab every 3 weeks (R-CHOP 21). It is looking at patients with newly diagnosed NHL. 

R-GCVP

Another trial is looking at a different chemotherapy regime called R-GCVP as a first treatment for diffuse large B cell lymphoma, for people who cannot have CHOP chemotherapy. R-GCVP is made up of rituximab, gemcitabine, cyclophosphamide, vincristine and prednisolone. This trial is now closed and we are waiting for the results. 

R-CODOX-M/IVAC

A trial is looking at another chemotherapy combination for people with diffuse large B cell lymphoma, if their doctor thinks there is a moderate or high risk of it coming back after treatment. This regime is called R-CODOX-M/IVAC, and it is really a combination of 2 chemotherapy regimes which you have alternately. R-CODOX-M is rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate. R-IVAC is rituximab, etoposide, ifosfamide and cytarabine. People on this trial will also have cytarabine injected into their spinal fluid (intrathecal injection), to try to stop the lymphoma spreading to the central nervous system. The researchers want to find out how well this chemotherapy combination works in stopping the lymphoma coming back, and to find out more about the side effects it causes.

R-CHOP-B

Doctors usually treat diffuse large B cell lymphoma (DLBCL) with a combination of drugs called R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone. A small trial called R-CHOP-B is looking at adding a type of biological therapy called bevacizumab to R-CHOP to see how helpful it is for this  group of patients. 

Chemotherapy for rare lymphomas

Doctors are also testing chemotherapy for rarer types of lymphoma. The WM1 trial is comparing the chemotherapy drugs fludarabine and chlorambucil for people with Waldenstrom's macroglobulinaemia, or lymphoma of the spleen. Fludarabine and chlorambucil are both effective treatments, but the researchers want to find out which one works best. The trial has closed and we are waiting for the results.

The EORTC 21012 trial is looking at how well liposomal doxorubicin works on its own for people with mycosis fungoides that has come back or has stopped responding after at least 2 courses of treatment. Mycosis fungoides is a type of cutaneous T cell lymphoma (CTCL), a rare group of non Hodgkin's lymphomas that affect the skin. This trial has now closed and we are waiting for the results.

The NHL 2006 01 trial is looking at treatment for children and young people (up to the age of 21) with anaplastic large cell lymphoma (ALCL) that has not responded to treatment or has come back. The trial aims to find out if chemotherapy, followed by a stem cell transplant, will be better at stopping ALCL from coming back than chemotherapy alone. It also aims to find out if vinblastine chemotherapy will help some children with ALCL that comes back after initial treatment. This trial is closed and we are waiting for the results. 

There is more information about these trials on our clinical trials database. Pick 'lymphoma' from the dropdown menu of cancer types.

New types of chemotherapy

Another new chemotherapy drug researchers have been looking into is bendamustine (Levact), which was licensed in the UK in September 2010. The National Institute for Health and Clinical Excellence (NICE) has not yet recommended bendamustine for use in England and Wales. The SMC have not recommended it as a treatment within the NHS in Scotland because the company making it have not put forward evidence to support its use. They may decide to put forward evidence in the future. But you may be offered it if your doctor thinks it is suitable for you. Researchers in America and Canada gave it to people with B cell lymphoma, who have had other treatments that were no longer working including rituximab. They found that it worked in over 6 out of 10 people (60%) who had already had chemotherapy. And on average it carried on working for at least 9 months. The side effects were similar to other chemotherapy drugs and included feeling sick, low blood counts, tiredness, diarrhoea and constipation. We need more research to confirm these results and trials are continuing.

NHL is often treated with radiotherapy. But doctors are aware that radiotherapy does have side effects that can be troublesome for people with NHL. There has been a trial to find out if a lower dose of radiotherapy can be just as effective for some people with NHL but have fewer side effects. We do not yet have the results from this study. Another trial is looking into lowering radiotherapy doses for people having treatment to relieve symptoms of follicular lymphoma. It's called the FORT trial. 

Biological therapies use substances that are produced naturally in the body or that change the way cells signal to each other. Some biological therapies can treat cancer. To look for biological therapy trials in NHL, go to our clinical trials database and pick 'lymphoma' from the dropdown menu. Biological therapies being used and studied in NHL include

• Rituximab
• Ibritumomab tiuxetan (Zevalin)
• Iodine-131 tositumomab (Bexxar)
• Epratuzumab (Lymphocide)
• Alemtuzumab (Campath)
• Ofatumumab
• I-CHT25
• Bevacizumab
• Drugs to reduce tumour blood supply
• Lenalidomide
• Bortezomib (Velcade)
• Romidepsin
• GSK461364
• Gene therapy

Rituximab

Rituximab is a type of monoclonal antibody therapy. This is one of the biggest advances in lymphoma treatments in recent years. An antibody treatment called rituximab is used to treat low grade and high grade B cell NHL. 

A Cancer Research UK funded phase 3 trial reported in 2011 that adding rituximab to chemotherapy increased survival time for newly diagnosed patients with mantle cell lymphoma (MCL). The Mantle Cell P3 trial compared rituximab and chemotherapy to the standard treatment of chemotherapy alone. It found that adding rituximab to fludarabine and cyclophosphamide chemotherapy increased survival by about 8 months. 

The rituximab versus watch and wait trial looked into whether giving rituximab to people with newly diagnosed follicular lymphoma can delay the time when they need to have chemotherapy and found that it did. 

Trials of rituximab are continuing to find the best ways to use it. The PACIFICO trial is looking at different combinations of chemotherapy and rituximab. The researchers want to find out which combination of rituximab and chemotherapy is best for follicular lymphoma in patients 60 years of age and older. It is comparing rituximab, cyclophosphamide, vincristine, and prednisolone (a steroid) with rituximab, fludarabine, and cyclophosphamide.

An international trial called PRIMA recently found that continuing with rituximab after finishing chemotherapy reduced the risk of follicular lymphoma coming back. 8 out of 10 of the people (80%) who had 2 monthly rituximab were still in remission after 2 years compared to just over 6 out of 10 (60%) who didn't have any treatment after their chemotherapy.

Ibritumomab tiuxetan (Zevalin)

Zevalin is a monoclonal antibody attached to a molecule of radioactive yttrium (pronounced it-ree-um) and often written as Y-90. Zevalin is licensed for use in the UK in people with CD20 positive follicular B cell NHL who have had rituximab, and either it hasn't worked or their NHL has come back since their treatment. Your doctor will need to consider whether Zevalin is suitable for you. They will take into account several things, including the specific type of lymphoma you have. Zevalin is not a cure for follicular NHL but it may help to control it. In July 2007, the Scottish Medicines Consortium (SMC) decided not to approve Zevalin for use in this way on the NHS in Scotland. They were not convinced that it was effective enough to justify its cost.

Zevalin has also been licensed in Europe as a maintenance treatment for follicular lymphoma in remission after the first course of treatment. Maintenance treatment is ongoing therapy aimed at keeping the lymphoma in remission. In August 2008, the SMC (Scottish Medicines Consortium) decided not to recommend Zevalin for this type of treatment on the NHS in Scotland. In May 2009 the All Wales Medicines Strategy Group also decided not to recommend for people in this situation.

Iodine-131 tositumomab (Bexxar)

Bexxar is a monoclonal antibody, attached to a molecule of radioactive iodine. The antibody finds the lymphoma cells and the attached radioactive molecule kills them. It has mostly been tried for low grade NHL that has come back or is proving difficult to treat. So far it seems to help get more people into remission, and may mean you are in remission longer. Bexxar is also being tried for high grade diffuse B cell lymphoma, the most common type of high grade lymphoma.

Epratuzumab (Lymphocide)

Epratuzumab (Lymphocide) is another type of monoclonal antibody that targets the CD22 protein found on B cells. It has been tested in people with high and low grade NHL that has come back or is proving difficult to treat. It has been tested on its own and in combination with rituximab.

Alemtuzumab (Campath)

Alemtuzumab (Campath) has been used in trials as a treatment for cutaneous T cell lymphoma. Now it is being tested in the CHOP-CAMPATH trial to see if giving it along with CHOP chemotherapy can help people with peripheral T cell lymphoma. This is a rare type of NHL where cancerous T cells circulate in the blood.

Ofatumumab

Ofatumumab is another monoclonal antibody targeting the CD20 protein. It is being used in a trial for people with diffuse large B cell lymphoma (DLBCL) who cannot have a transplant of their own stem cells, or who had a transplant but the lymphoma came back or continued to grow. Ofatumumab attaches to the CD20 proteins on the B cells, allowing your immune system to find and kill them. This trial has now closed and we are waiting for the results.

The ORCHARRD study is comparing ofatumumab to rituximab for people who have DLBCL or follicular lymphoma that has come back. They want to see if ofatumumab works better than rituximab for people having treatment for the second time. In this study doctors are comparing DHAP chemotherapy and rituximab treatment with DHAP chemotherapy and ofatumumab, followed by a stem cell transplant.

I-CHT25

CHT25 is a monoclonal antibody that targets the CD20, or IL-2, receptor found on some lymphoma cells. I stands for Iodine-131. So I-CHT25 is the CHT25 antibody attached to a radioactive iodine molecule. Doctors hope that the CHT25 will bind to the IL-2 receptors on the lymphoma cells, and the radioactivity will kill the cells. An early phase 1 trial found a safe dose of I-CHT25 that didn’t cause serious side effects. They also found that the drug helped about two thirds of the people in this trial.  The researchers are now planning a phase 2 trial.

Bevacizumab

Bevacizumab (Avastin) is also a type of monoclonal antibody. It targets a protein made by cells called vascular endothelial growth factor (VEGF).  This stops the lymphoma from developing the blood vessels that it needs to grow. The R-CHOP-B trial is looking at giving R-CHOP chemotherapy with bevacizumab to treat people with diffuse large B cell lymphoma. 

Drugs to reduce tumour blood supply

Doctors call this type of treatment anti angiogenic treatment. Angiogenesis means growth of new blood vessels. Cancers need to grow their own blood vessels as they get bigger. Without its own blood supply, a cancer cannot continue to grow.

Thalidomide is an anti angiogenic drug. Thalidomide got a bad reputation in the 1950s and 60s for causing birth defects. But it only causes problems if taken in pregnancy.

Thalidomide has been shown to slow the growth of cancer cells in some cancers, such as myeloma. Studies are now in progress looking into using thalidomide and other anti angiogenesis drugs for lymphoma. These types of treatments may eventually be useful to treat some types of NHL. But some researchers believe that they will only be useful in combination with other treatments already available, such as chemotherapy, radiotherapy and biological therapy.

A trial is looking at whether thalidomide can help to control angioimmunoblastic lymphoma, a rare type of T cell lymphoma, after chemotherapy. There is more information about this trial in the chemotherapy for rare lymphomas section on this page.

Another anti angiogenic drug is enzastaurin. The PRELUDE trial is looking to see if enzastaurin can help stop diffuse large B cell lymphoma coming back after chemotherapy, or keep it under control for longer. This trial is now closed and we are waiting for the results. 

Lenalidomide (Revlimid)

Lenalidomide is another type of biological therapy. It works mainly by helping the body’s immune system target cancer cells. The EMERGE trial is looking at lenalidomide for people who have mantle cell non Hodgkin’s lymphoma. It is for people who have been treated with bortezomib (Velcade). Doctors often treat mantle cell lymphoma with chemotherapy. If mantle cell lymphoma comes back, doctors are not sure what to treat it with and have few treatments to choose from. The aim of this trial is to find out if lenalidomide can help people with mantle cell lymphoma after having bortezomib

Bortezomib (Velcade)

Bortezomib is a proteasome inhibitor. This means that it interferes with the chemicals inside cells, making proteins build up and kill the cells. Cancer cells are more sensitive to proteasome inhibitors than normal cells. There is a trial looking at giving bortezomib with CHOP chemotherapy for mantle cell lymphoma. Researchers want to find out if this works better than just the chemotherapy on its own. Another small trial is looking at giving bortezomib in combination with other treatments. 

The REMoDL-B trial is trying to find out if bortezomib can help to stop diffuse large B cell lymphoma (DLBCL) coming back after treatment. The standard treatment for DLBCL is R-CHOP, a combination of chemotherapy and a monoclonal antibody called rituximab. For many people, R-CHOP gets rid of the lymphoma cells (gets it into remission). But sometimes DLBCL does not go away, or comes back. This trial wants to see if adding bortezomib to R-CHOP will make it work better. 

There is information about these trials on our clinical trials database.

Romidepsin

Romidepsin (also called depsipeptide or FK228) is a new type of drug called a histone deacetylase inhibitor. It is made from a type of bacteria and works by stopping cells from dividing and growing. Doctors in the UK have tried romidepsin in a trial to see if it is effective for cutaneous T cell lymphoma (CTCL) that has continued to grow during treatment or has come back. Cutaneous T cell lymphoma is a rare type of non Hodgkin's lymphoma that affects the skin. We are now waiting for the results of the trial. You can find more information about it on our clinical trials database.

In America, two clinical trials found that romidepsin controlled CTCL for between 1 and 20 months in about a third of people who had the treatment.  The Federal Drugs and Administration (FDA) have now approved it in America for people who have had other treatments which are no longer working. But before people can have it as a treatment in the UK it needs to be licensed and it may be a while before this happens. You can find out more about how drugs are licensed in our question and answer section. 

GSK461364

This is another type of inhibitor drug. It stops an enzyme called PLK1 working. If PLK1 isn't working properly, then the lymphoma cells can't divide, so this could be a way of slowing down or stopping the lymphoma. There is a phase 1 trial for people with non Hodgkin's lymhoma which has continued to grow despite having all the standard treatments available. Doctors want to find out what the best dose and treatment schedule is, and what the side effects of this new drug are. It is also being tried out for people with other types of cancer. The trial has now closed and we are waiting for the results.

Gene therapy

Gene therapy aims to change the genes in cells in ways that will attack the cancer. This could be by 

• Stopping genetic changes 
• Replacing the altered genes of cancer cells
• Further changing the genes of the cancerous cells so that they are easier to destroy
• Changing the genetic make up of a virus so that it attacks cancer cells, but not normal cells

There is a small trial of gene therapy for B cell non Hodgkin's lymphoma that has a protein called CD19 on the cell surface. Doctors want to take T cells from the blood of people with this type of NHL. Then they want to genetically alter the T cells. So when the T cells are put back into the body they will recognise the CD19 protein on the lymphoma cells and attack them. These altered T cells are called aCD19z cells. Patients on this trial will also have chemotherapy to kill off immune system cells that might attack the aCD19z cells. They will also have interleukin 2 (IL-2), which the researchers hope will make the genetically altered T cells live longer and work better. 

You can find more information about all these UK trials on our clinical trials database. Pick 'lymphoma' from the dropdown menu.

Studies are looking at improving the way stem cell transplants are carried out for people with NHL.

It is possible to have treatment with your own stem cells. This is called an autologous transplant. But there is a risk that, after their treatment, the cells given back to you may still include some lymphoma cells. Scientists are trying to find new ways of getting rid of these from the stem cells. Research suggests that some of the new biological therapy drugs, such as rituximab, may help to remove these last remaining lymphoma cells. Doctors have been testing rituximab before and after autologous transplant for low grade lymphoma. They want to find out if this treatment will help keep the lymphoma in remission for longer. This trial closed in April 2006, and we are waiting for the results.

Another trial is looking into using high dose chemotherapy and autologous stem cell transplant to treat T cell lymphoma of the small bowel. This is a very rare form of non Hodgkin's lymphoma that is usually treated with chemotherapy on its own. You can find more information about this trial on our clinical trials database.

A procedure called a mini transplant has been investigated for people with NHL. In mini transplant, the chemotherapy doses are not high enough to destroy all your bone marrow cells. This can make it possible to treat some patients older than 50 because the side effects are less severe than those of a standard bone marrow transplant.

After the chemotherapy, you have bone marrow or stem cells from someone else (a donor) instead of your own marrow or stem cells. The idea is that the donor marrow cells will replace your surviving bone marrow cells and make antibodies that will kill off the NHL cells. But the donor cells can also attack normal cells in the body. This is called graft versus host disease (GVHD).

Some people with NHL 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 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 lymphoma cells left behind – something called the graft versus lymphoma (GvL) effect.

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. These cord blood 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.

The EORTC 21011 trial  is looking to see whether a drug called bexarotene (also called Targretin) can be effective in treating people with early stages of mycosis fungoides (a form of cutaneous T cell lymphoma, a rare group of non Hodgkin's lymphomas that affect the skin). Bexarotene is a new type of retinoid drug. Retinoids contain chemicals that are similar to vitamin A. A treatment called PUVA is commonly used to treat mycosis fungoides. Although this treatment works well at first, the cancer usually comes back (recurs) and then you need more treatments with PUVA. If you have repeated courses of PUVA, your risk of developing non-melanoma skin cancer increases. Doctors would like to be able to reduce the dose of PUVA and so reduce this risk. So the trial compares giving PUVA alone with giving PUVA and bexarotene. This trial is now closed and we are waiting for the results. 

Another trial is looking at how well bexarotene and the chemotherapy drug gemcitabine work for cutaneous T cell lymphoma (CTCL) that has got worse despite having had treatment to the skin and systemic treatment like interferon or chemotherapy. You may be able to join this trial if you are in this position, and you have stage 1b, 2, 3 or 4a CTCL.

Often after treatment for lymphoma, the disease appears to have gone. No lymphoma cells can be seen in your blood and bone marrow samples and you are said to be in remission. But there are often lymphoma cells left behind. This is called minimal residual disease (MRD). Scientists are exploring new ways of finding out if there are lymphoma cells left behind after the disease appears to have clinically gone - in other words, is in remission. These tests can help your doctors to find out how effective your chemotherapy has been in killing off all of your lymphoma cells. This test can help to tell the doctor whether your lymphoma is likely to come back (relapse).

Many tests are used, including 

• Flow cytometry (a specialised microscope to look for markers on cells in your blood and bone marrow)
• Immunohistochemistry testing (a test for staining cells to see what's in them)
• Polymerase chain reaction (PCR  ̶̶  a way of making copies of DNA)

Another test is PET scanning or positron emission tomography. After radiotherapy or chemotherapy has shrunk a tumour, harmless fibrous tissue can be left behind. On a CT scan, it may not be possible to tell if this tissue is fibrous or if it contains active lymphoma cells. It seems, from some very small studies, that PET scanning is able to do this. If doctors could check this with a scan, they would be able to tell more easily who needed more treatment and who didn't.

Although PET scanning is fast becoming one of the most important techniques used in helping to diagnose and manage many types of cancers, more research is needed before we know how important it will be in monitoring the treatment of NHL. There are a limited number of PET scanners throughout the UK as they are relatively new and very expensive. But your doctor will refer you to have a PET scan at your nearest centre if you need to have one done. 

If you are interested in taking part in a clinical trial, you need to ask your own specialist if you may be suitable for any studies. Lymphoma is a big area of cancer research and most major treatment centres are continually involved in clinical trials.

There is a study looking at the abnormal lymphocyte cells found in the blood of people with lymphomas and other diseases. Scientists are trying to understand how a particular gene helps these abnormal cells to survive. If you have follicular lymphoma, mantle cell lymphoma or a rare type of lymphoma called splenic lymphoma with villous lymphocytes (SLVL), 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 people with lymphoma and other types of cancer in the future.