Helpline 0808 808 5555

Mantle cell lymphoma

 By Dr Simon Rule, Derriford Hospital, Plymouth

Dr Rule qualified from Nottingham medical school in 1987. As a medical student he was awarded a Master of Philosophy degree for research into chronic myeloid leukaemia. He trained in Haematology in London at the Westminster and Hammersmith hospitals and spent some time as a senior registrar in Australia.  He is currently a consultant in Derriford Hospital where he is head of the clinical service and runs all clinical trial work.

Dr Rule is a member of the National Cancer Research Network (NCRN) lymphoma and CML working parties, chairman of the Peninsula network haemato-oncology group. His major interests are lymphoma, leukaemia and new drug development. His specific area of interest is in mantle cell lymphoma and he has a research team looking at various aspects of this disease. In addition he chairs the NCRN Mantle Cell Lymphoma trial group and he is currently the principal investigator for a number of phase 2 and phase 3 lymphoma studies being conducted at local, network and national level.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin lymphoma accounting for approximately 1 in 20 of all cases. This is a relatively new addition to this group of diseases, having been specifically recognised and named in 1992. Prior to that it went by a variety of names and was considered a ‘low grade’ lymphoma, although we now recognise it as an aggressive disease.

The term mantle cell was applied because the lymphoma cells arise from a particular part of the normal lymph node, called the mantle zone. The key to diagnosis is finding a specific problem with the genes within the tumour. In MCL an abnormality occurs in a cell when two chromosomes which we know as ‘11’ and ‘14’ break and then join each other, producing what is called a translocation. The result of this translocation is that the new arrangement of DNA coding created over-produces a protein that is involved in controlling cell growth. With unregulated growth the mantle zone cells proliferate and this ultimately leads on to the development of the lymphoma.

Cause of mantle cell lymphoma

As with many forms of lymphoma the cause is not known. There are no particular environmental or geographical associations but it is strikingly more common in men than women and is seen up to 5 times more frequently in males. MCL can become obvious in a number of ways. Most patients go to their doctor with rapid enlargement of lymph glands, as commonly seen with the aggressive lymphomas.  The bone marrow is usually involved and the disease can mimic a common form of leukaemia (chronic lymphocytic leukaemia) with lymphoma cells found in the blood stream. One of the classical features of MCL is its tendency to affect the bowel, sometimes presenting as a change in bowel habit or even mimicking a bowel disorder such as Crohn’s disease. Even in patients with no symptoms of bowel problems, most will have the disease present in the bowel wall if it is looked for.

Diagnosis

MCL is often difficult to diagnose and may not be obvious until what was thought to be an indolent lymphoma or even chronic lymphocytic leukaemia relapses early or fails to respond to conventional therapies. This is because the MCL cells do not look aggressive when looked at down the microscope, and the additional testing that is needed to make the diagnosis may not be undertaken initially. The chromosomal translocation that is the hallmark of the disease is often difficult to pick up although the protein that this leads to is easy to demonstrate.

Treatment

This is a difficult disease to treat and with the possible exception of an allogeneic bone marrow transplant (using donor bone marrow) it is not curable. MCL tends to behave in an aggressive way and consequently is often treated as such. Many types of chemotherapy produce responses in MCL but these are often incomplete and do not last very long. CHOP chemotherapy, which is standard in aggressive lymphomas is often used but is not very effective with about one third of patients getting a good response. More aggressive chemotherapy treatments do increase response rates but the treatments are very toxic and so are reserved for fitter, which usually means younger, patients. Stem cell (bone marrow) transplantation is being used more frequently in younger patients and is subject to a number of on-going trials overseas.

There are two different forms of transplantation that can be used in this disease. Autologous transplants involve transplantation of the patient’s own cells back into themselves following the use of high dose chemotherapy and/or radiotherapy. This almost certainly does not lead to a cure but may increase the time that the disease remains in remission; however, the procedure itself is dangerous with approximately 1-5% patients dying as a consequence. An allogeneic transplant involves taking stem cells from another individual and putting them into the patient following chemotherapy and/or radiotherapy. This is a much more difficult procedure that can only be performed in specialist units. The chance of dying following such a transplant is at least 10% and can be much higher depending on a number of factors such as how close the match is and the age and fitness of the patient. Because of these risks most transplants are performed on patients under the age of 50 years.  Some patients still relapse following an allogeneic transplant but this remains as probably the only curative treatment available at the moment. 

A UK pilot trial on the use of reduced intensity allogeneic transplants for younger patients with MCL is planned and should start at some point this year. This is a newer form of transplant that appears safer and less toxic but there is not much experience with it in mantle cell disease as yet.

The majority of patients with mantle cell lymphoma are elderly with an average age at presentation (when they first go to their doctor with symptoms) in the mid-60’s.  In this group, knowing it is difficult to obtain remissions, and because the disease is incurable, if the patient is clinically well it can be a good idea to watch and wait and only commence some therapy when symptoms become troublesome.

In this group of patients there are a number of different treatment options which include many of the conventional therapies used in the indolent (low grade) lymphomas and chronic lymphocytic leukaemia, such as oral chlorambucil and cyclophosphamide. More intense treatments can be used depending on the fitness of the individual. As a general rule more intense treatments increase response rates but have more side-effects and can be difficult to tolerate in more elderly patients.

Trials and future considerations

As mantle cells have the CD20 antigen expressed on their cell surface the monoclonal antibody rituximab has been used. When used on its own it is not very effective producing short-term responses in about one third of patients, which is not as good as the responses seen in other forms of lymphoma. In combination with chemotherapy it may be more effective than chemotherapy alone but this has yet to be proven conclusively in clinical trials.

At the moment the UK is running a large trial to see if the addition of rituximab to chemotherapy does improve responses. This is a randomised study for newly diagnosed patients (half of the patients will receive rituximab in addition to chemotherapy the other half just the chemotherapy) and should be open in all hospitals in the UK (including Scotland). The National Institute of Clinical Excellence (NICE) have not looked at the use of rituximab in mantle cell either as a single agent or in combination with chemotherapy and so it is not widely available.

There are a number of potential treatments that are currently at the trial stage. Velcade is a new class of drug called a proteosome inhibitor that has recently been licensed in the USA for a form of bone cancer called myeloma. This disease shares some similarities with MCL, particularly in the treatments that seem to work. Early clinical trial work in the lymphomas suggests that Velcade may be particularly useful in MCL. A large study which aims to prove this is on-going in the United States and will soon be open in certain hospitals in the UK.  Thalidomide is a sedative drug that was banned in the 1960’s when severe birth defects were found to be caused by its use. It, too, is being used in myeloma but early work from the UK suggests that it may be active in up to one third of patients with previously treated MCL. It is unclear as to how this drug works in this situation. A small trial to assess its use in MCL is due to start soon in the UK.

On the horizon are a number of potential new drugs being developed. These have yet to be tested in patients but are being designed to work specifically against certain factors within the lymphoma cells themselves. These are some years off but offer hope of therapies that will be more effective and less toxic than the current treatments.

Glossary

Chromosome- a small ‘package’ of genes or DNA codes in the nucleus of a cell. The DNA codes are ‘translated’ into the body’s proteins.

Proteosome - an enzyme complex that is present in all cells. Its function is to break down proteins that are involved in the internal workings of the cell in order to regulate growth. Velcade stops this process for a short time, this does not affect normal cells but many types of cancer cells do not survive.