Mantle cell lymphoma. What is lymphoma? What kinds of lymphoma are there?

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1 Freephone helpline Mantle cell lymphoma Mantle cell lymphoma (MCL) is a rare form of lymphoma, accounting for approximately 1 in 20 of all non-hodgkin lymphomas. This is a relatively new addition to this group of diseases, having been specifically recognised and named only in In this article we are aiming to: explain what mantle cell lymphoma is describe what symptoms you might experience outline how mantle cell lymphoma is diagnosed describe the treatments that are currently available for this kind of lymphoma give you an update on new treatments that are being developed. What is lymphoma? Lymphomas are cancers of the lymphatic system. The lymphatic system is a complex network of fine tubes (lymphatic vessels), glands (lymph nodes) and other organs including the spleen and thymus gland. Lymph nodes are found throughout the whole body, but mainly in the neck, armpits, groin, chest, abdomen and pelvis. The fluid (lymph) that circulates through the lymph vessels and nodes carries with it specialised white blood cells called lymphocytes, which are manufactured in the bone marrow and which help the body to fight infections. A lymphoma develops when some of these lymphocytes start to grow out of control or don t die off after their normal lifespan. These abnormal cells can then build up in lymph nodes, in the bone marrow or in the spleen and sometimes in other places in the body. What kinds of lymphoma are there? There are two main types of lymphoma, Hodgkin lymphoma and non-hodgkin lymphoma (these are all the lymphomas that aren t Hodgkin lymphoma). Mantle cell lymphoma is one type of non-hodgkin lymphoma. Lymphomas are also described as being either high grade (or aggressive ), when the cells appear to be dividing quite quickly, or low grade (or indolent ), when the cells appear to be dividing more slowly. It is important to find out whether a lymphoma is high grade or low grade because they are treated differently. 1/7

2 What is mantle cell lymphoma? MCL was initially described as a low-grade lymphoma because of how it looks under the microscope. However, it behaves more like a high-grade lymphoma in most cases and so is treated as an aggressive lymphoma. The term mantle cell is used to describe this lymphoma because the lymphocytes that have become cancerous arise from a particular part of the normal lymph node called the mantle zone. A lymph node Afferent lymphatic vessels Capillary Mantle zone Germinal centre of follicle Vein and artery Efferent lymphatic vessel (Science Photo Library / C ) The mantle zone is a covering layer of lymphocytes that surrounds the central part or germinal centre of the lymph node s follicles. These follicles normally develop and become active in the lymph node when the body recognises a foreign invader such as a bacterium and is mounting an immune response to it. As with many forms of lymphoma, the cause of MCL is not known, but the key to making the diagnosis is finding a specific problem with the genes within the lymphoma cells. In MCL an abnormality occurs when two chromosomes (chromosome 11 and chromosome 14) break and then join up with each other, producing what is called a translocation. The result of this translocation is that the new arrangement of DNA coding created leads to the production of too much of a protein that is normally involved in controlling cell growth. Because of this unregulated growth the mantle zone cells proliferate and this ultimately leads on to the development of the lymphoma. Who gets mantle cell lymphoma? There are no particular environmental or geographical factors that make MCL more likely to develop, but it is strikingly more common in men than it is in women this lymphoma is seen up to two to three times more frequently in men. The cause of MCL is not known. 2/7

3 Symptoms of mantle cell lymphoma MCL can become obvious in a number of ways, but most people go to their doctor because they have noticed swellings of their glands due to rapid enlargement of lymph nodes, as is 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 bloodstream. One of the classic features of MCL is its tendency to affect the bowel. It sometimes first becomes apparent as a change in bowel habit, for example with worsening diarrhoea. Because of this it can be mistaken for a bowel condition such as Crohn s disease. Even people with no symptoms of bowel problems will be found to have MCL in the bowel wall if it is looked for by specialised tests. How is mantle cell lymphoma diagnosed? MCL can be difficult to diagnose and the true diagnosis might not become obvious until what was thought to be a slow-growing 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 under the microscope and the additional testing that is needed to make the diagnosis might not be undertaken initially. The chromosomal translocation that is the hallmark of the disease is often difficult to pick up, although the protein that is formed as a result of this change in the genetic make-up shows up more readily in tests. Once a diagnosis has been made, people with MCL will have the same investigations that people with the more common lymphomas need to assess their lymphoma standard blood tests, together with a bone marrow biopsy and a computed tomography (CT) scan. There is no need to specifically examine the bowel if there are no bowel symptoms because finding MCL in the bowel does not affect the treatment. Another kind of scan, which is used for people with some other types of lymphoma, positron-emission tomography (PET), is not part of the routine assessment in MCL at the moment but is being evaluated to see if it might be helpful. How is mantle cell lymphoma treated? Chemotherapy This is a challenging disease to treat and with the possible exception of an allogeneic stem cell transplant (using donor stem cells) it is not curable. MCL tends to behave in an aggressive way and so is often treated as if it was a high-grade lymphoma. Many types of chemotherapy can be used in MCL but these treatments often only lead to an incomplete response which does not last very long. A combination of four drugs which is used as a standard treatment in aggressive lymphomas cyclophosphamide, hydroxydoxorubicin, Oncovin (vincristine) and prednisolone, known as CHOP is often used to treat MCL but is not as effective as it is in these other forms of lymphoma. More aggressive chemotherapy regimens do lead to better responses to treatment but these therapies are very toxic and so are reserved for fitter, which usually means younger, patients. 3/7

4 Stem cell transplants Stem cell transplantation is being used more frequently in younger patients with MCL and this form of treatment is being studied in a number of ongoing clinical trials overseas. When you have a stem cell transplant you first have high doses of chemotherapy (and sometimes radiotherapy) to kill off all the lymphoma cells. This causes permanent damage to the bone marrow as a side effect and you then need a transfusion (or transplant) of stem cells to allow your bone marrow to recover. Stem cells are primitive cells from the bone marrow which have the potential to mature into normal blood cells. Stem cell transplants are complicated and specialised treatments and carry considerable risks as well as benefits. These would be explained to you if your medical team was considering this form of treatment. There are two different forms of transplantation that can be used in MCL: autologous stem cell transplantation allogeneic stem cell transplantation. Autologous transplants involve using your own stem cells, which are collected from you before you have the course of high-dose chemotherapy and/or radiotherapy. This type of transplant almost certainly will not lead to a cure but does increase the time that the lymphoma remains in remission. A large research study in Scandinavia has shown that using quite intensive chemotherapy (similar to that used in forms of acute leukaemia) followed by an autologous transplant leads to very good results in people whose lymphoma is sensitive to the chemotherapy. In this study 70% of patients were still alive 6 years after the treatment. Allogeneic transplants involve taking stem cells from another person (ie a donor) and transfusing these after the high-dose chemotherapy and/or radiotherapy. Although allogeneic transplants do offer the possibility of cure, it is a difficult and risky procedure that can only be performed in specialist units. The risks are higher if a closely matched donor is not available or when the patient is in poor general health. Because of these risks most allogeneic transplants are performed in patients under the age of 60 years. Some people will still relapse even after having an allogeneic transplant, but this is probably still the only curative treatment available at the moment. A UK pilot trial on the use of reduced-intensity allogeneic transplantation for younger patients with MCL is currently ongoing in this country. This is a newer form of transplant that involves less intense treatment and it appears to be safe and less toxic. There is not much experience with it in mantle cell lymphoma as yet, but this is a hopeful development. Treatment of older patients The majority of people with MCL are in the older age bracket. The average age at which people usually first go to their doctor with symptoms is the mid-60s. Because MCL is not curable and remission can be difficult to obtain with the currently available treatments, it can be a good idea to adopt a watch and wait approach for older patients who do not have symptoms. This means that therapy only begins when symptoms become troublesome. 4/7

5 Once the medical team decide that it would be appropriate to start some treatment, there are various options, including many of the conventional therapies used in the treatment of low-grade lymphomas and chronic lymphocytic leukaemia, such as oral chlorambucil or cyclophosphamide. More intense treatments can also be used, depending on how good your general health is. This is because, as a general rule, although more intense treatments can be more successful, they cause more side effects and older people can find these difficult to tolerate. Clinical trials and future considerations As mantle cells have a protein called CD20 on their cell surface, a specialist kind of treatment called a monoclonal antibody can be used to target this protein on the lymphoma cell. The monoclonal antibody often used to treat other kinds of lymphoma, rituximab, has been used in MCL. When used on its own it is not very effective, producing a short-term response in only about a third of patients. This is not as good as the response seen in other forms of lymphoma. However, in combination with chemotherapy it might be more effective than chemotherapy alone (though this has yet to be proved conclusively in clinical trials). The UK has just completed a very large clinical trial to see if the addition of rituximab to chemotherapy does improve the response to treatment. In this trial half the patients received chemotherapy plus rituximab and half received chemotherapy alone. This trial involved 380 patients and the results will be available at the end of However, the National Institute for Health and Clinical Excellence (NICE) has not yet looked at the use of rituximab in mantle cell lymphoma, either on its own or combined with chemotherapy, and so its availability will still vary around the country. There are a number of new treatments becoming available for MCL, some of which are currently at the trial stage. One possible treatment for the future is bortezomib (Velcade ), which is a new kind of drug that acts against a substance in the lymphoma cell called a proteosome. Proteosomes break down proteins that are involved in the internal workings of the cell in order to regulate growth and Velcade stops this for a while. This drug is used widely for a form of cancer called myeloma and NICE has approved its use for myeloma in the UK. Velcade has a licence in the USA for the treatment of MCL on the basis of a large study which showed a response to treatment in about a third of patients when they were treated with Velcade alone. This drug will not be available in Europe until further trials have been undertaken, however. Further trials with Velcade in combination with rituximab and other chemotherapy drugs are ongoing and these combinations might prove to be useful. A UK National Cancer Research Network (NCRN) trial is currently looking at the addition of Velcade to CHOP chemotherapy in patients whose lymphoma has relapsed. The only licensed drug for MCL in Europe is temsirolimus. This is a drug which interferes with the chemical pathways that signal mantle lymphoma cells to grow. This drug reduces the lymphoma in about 30% of patients. It has to be given directly into the bloodstream by intravenous drip once a week. It has not been endorsed by NICE and so is not an agent that is generally available. 5/7

6 Thalidomide is a sedative drug that was banned in the 1960s when it was found to cause serious birth defects. It, too, is being used in myeloma but early work from the UK suggests that it might be effective in up to a third of patients with previously treated MCL. It is unclear how this drug works in MCL. A new thalidomide-like drug has recently been produced called lenalidomide. This looks as if it will be more effective than thalidomide itself, with over 40% of people showing a good response to treatment, with fewer side effects than thalidomide. On the horizon are a number of potential new drugs under development. Some of these are being tested in early clinical trials and appear to be effective against MCL, though this is not yet certain. There are currently trials of some of these drugs being conducted in the UK and details of these trials are available from the Plymouth Mantle Cell Lymphoma Trials Unit website (see below). In addition there are a host of other treatments that are at earlier stages of development. 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 away but offer hope of therapies that will be more effective and less toxic than the current treatments. Acknowledgement We are grateful to Dr Simon Rule, consultant haematologist at Derriford Hospital, Plymouth, for writing this article. Dr Rule chairs the NCRN Mantle Cell Lymphoma trial group and runs a trial unit in Plymouth specifically for patients with MCL. He commonly sees and advises patients on treatment options who have been referred to him from other centres in the UK. More information The Lymphoma Association produces a wide range of booklets and information sheets on all aspects of lymphoma and its treatment. Visit our website at or telephone our freephone helpline on if you would like to receive any of this information or if you would like to talk to someone about your lymphoma. Useful organisations Mantle Cell Lymphoma Trials Unit Tamar Science Park Room N14 ITTC Building Plymouth PL6 8BX via website 6/7

7 Leukaemia & Lymphoma Research Dedicated exclusively to researching blood cancers, including leukaemia, lymphoma and myeloma Eagle Street London WC1R 4TH (Mon Fri, 9am 5pm) Macmillan Cancer Support Exists to improve the lives of those affected by cancer by providing practical, medical, emotional and financial help as well as pushing for better cancer care. 89 Albert Embankment London SE1 7UQ via website References Galimberti S, Petrini M. Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma. Cancer Management and Research, : Habermann TM, et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. British Journal of Haematology, : Geisler CH, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a non-randomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood, : Fisher RI, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Journal of Clinical Oncology, : This publication should not be used for medical diagnosis or treatment and is for information only. Although the Lymphoma Association has taken great care in researching and putting such information together, we cannot give any warranties as to its accuracy. Please consult a medical professional if you have concerns about your health or treatment. See for our full disclaimer. Lymphoma Association PO Box 386, Aylesbury, Bucks, HP20 2GA Produced Due for revision /7