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Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia (CLL) is a cancer of lymphocytes, which are specialised blood cells that are involved in the body’s immune system. Although its name includes the word ‘leukaemia’ (because these malignant blood cells are found in the bone marrow and circulating in the bloodstream), CLL is now officially classified by the World Health Organisation as a low-grade (slow-growing) non-Hodgkin lymphoma. In a closely related condition, small lymphocytic lymphoma or SLL, the malignant cells are mainly found in the lymph nodes (glands), as in most other lymphomas. There is more information on SLL on page 2. CLL used to be thought of as a disease which mainly affected older people and which had fairly limited treatment options. However, these ideas have completely changed over the last 10–15 years – the modern perception of CLL is that it is a complex disease that can affect adults of all ages and which comes in many different forms. Most importantly, there is now a wide range of treatment options. This article is aiming to answer the main questions that people with newly diagnosed CLL might ask: ●
What is CLL and what causes it?
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What are the symptoms?
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How is CLL diagnosed and what do the ‘stages’ mean?
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How might CLL affect me?
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What are the treatment options – when to start, what to have, when to stop?
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What happens after treatment?
CLL is a complex disease and this article is aiming to provide an introduction to it. Further information can be obtained from the websites run by the CLL Support Association (www.cllsupport.org.uk) and Leukaemia & Lymphoma Research (www.leukaemialymphomaresearch.org.uk), which are both based in the UK, and from CLL Topics, which is based in the US (www.clltopics.org). See page 12 for contact details. Because CLL is a disease that people often live with for many years you might also find our booklet Living with lymphoma helpful. It covers the more everyday aspects of living with a chronic malignant condition like CLL, such as how to cope with tiredness and other symptoms, your feelings and relationships, diet and exercise and other practical things like managing medical appointments, financial matters, travel and vaccinations.
What is CLL? CLL is a type of cancer that affects the body’s immune system. Like all cancers, the disease begins as a single cell that goes wrong in a way that makes it divide and survive inappropriately past its normal lifespan – one cell divides into two, two into four, four into eight, and so on. Chronic lymphocytic leukaemia
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Eventually the body ends up with billions of these abnormal cells, which slowly accumulate in the blood, bone marrow, lymph nodes, liver and spleen. As more and more CLL cells accumulate, they can release chemicals which cause tiredness, weight loss and sweating. If they accumulate in the bone marrow they can also stop your bone marrow from working properly. Because the bone marrow is the ‘factory’ that makes normal blood cells that circulate round the body in the bloodstream, this can cause you to develop: ● ●
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anaemia, due to a reduction in the numbers of red blood cells thrombocytopenia, meaning a reduction in the number of platelets, which normally help the blood to clot – this can therefore mean that you bruise or bleed easily neutropenia, a reduction in healthy white blood cells, which increases your risk of infection.
The exact nature of the malignant CLL cell is still not entirely clear but it is thought to be a special type of lymphocyte called a ‘marginal zone B cell’. Normally these B cells play an important role in maintaining a healthy immune system. However, the accumulation of large numbers of CLL cells stops the immune system from working properly. There are two consequences of this: ●
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The immune system does not react properly against the things it should react against (such as bacteria and viruses). This increases the risk of these organisms causing infections. The immune system can start to react against things it should not react against, including your body’s own cells. This is called autoimmunity and in CLL it can mean that your immune system reacts against some of your blood cells. When the immune system attacks your healthy red blood cells you can become anaemic – this is called ‘autoimmune haemolytic anaemia’ or AIHA for short. When it attacks platelets you can become more prone to bruise or bleed easily and you might notice small red spots of bleeding just beneath the skin of your lower legs – this is called ‘immune thrombocytopenic purpura’ or ITP for short.
Conditions that are similar or related to CLL Small lymphocytic lymphoma As we described earlier, there is a condition related to CLL called small lymphocytic lymphoma (SLL), in which the abnormal cells accumulate mainly in the lymph nodes, with few being found in the bloodstream (in contrast to classic CLL). If this lymphoma remains in the lymph nodes radiotherapy treatment can be targeted to areas where there are affected nodes. This disease often goes on to involve the blood too, however, when it behaves in a very similar way to classic CLL. When this happens the treatment of the two conditions is the same.
Richter syndrome Rarely (in fewer than 1 in 10 people), CLL can turn into (or ‘transform’ into) a faster-growing type of lymphoma called diffuse large B-cell lymphoma and when this happens it is called ‘Richter transformation’ or ‘Richter syndrome’ (see page 5). This requires treatment with different chemotherapy from that used for treating classic, untransformed CLL. Occasionally, therefore, it is necessary for your doctors to perform a lymph node biopsy during the course of having classic CLL to rule out the development of Richter syndrome. Chronic lymphocytic leukaemia
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Hairy cell leukaemia Hairy cell leukaemia (HCL) has a few similarities to CLL but this is a separate condition – the cells look quite different under the microscope, it behaves differently and it is treated differently. We have a separate information sheet on hairy cell leukaemia, so please ask the helpline for a copy if you would like more information on this type of lymphoma (0808 808 5555).
What causes CLL? The cause of the changes that take place in the CLL cells to make them malignant – and so the cause of CLL developing – is not known, but there are a few factors that are known to increase the risk of it developing: ●
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Older age – most people are aged over 60 when they are diagnosed; it is rare in people aged under 40. Male sex – nearly twice as many men are diagnosed with classic CLL compared with women. Genetic factors – around 1 in 10 people diagnosed with CLL will have a family member who also has this type of lymphoma. Tests that predict whether or not individual family members are likely to develop CLL are not currently available but the important thing to remember is that most people who have a relative with CLL will never develop it themselves. European ethnicity – CLL is more common in Europeans and is rare in people of Asian origin.
What are the symptoms of CLL? In around 75% of people with CLL the condition is discovered quite by chance, for example when a blood test is done for something else, and about 50% of people with CLL will have no symptoms whatsoever. Because of the chemicals the CLL cells release and the effects of the CLL cells on the bone marrow and the immune system, however (see page 2), you might experience a variety of symptoms, such as: ●
tiredness or a feeling of being generally unwell
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proneness to develop infections
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enlarged lymph nodes (producing lumps in the neck, armpit or groin)
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an enlarged spleen, causing tenderness in the upper left-hand side of the abdomen
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breathlessness (due to anaemia)
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a tendency to bruise or bleed easily (due to a low platelet count in the blood)
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night sweats
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weight loss.
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How is CLL diagnosed? CLL is usually diagnosed by looking at the cells in your blood. It is suspected when the blood count shows large numbers of lymphocytes. These CLL cells have a distinctive appearance when viewed under the microscope. The diagnosis is confirmed by a technique called ‘immunophenotyping’. This involves the detection of characteristic proteins (or ‘antigens’) on the surface of the lymphocytes. The abnormal lymphocytes’ chromosomes are also sometimes analysed (this is called cytogenetic testing or FISH testing). The diagnosis of SLL may require a lymph node biopsy, when a lymph node is removed after the skin over it is numbed with a local anaesthetic. The biopsy specimen is taken to a pathology laboratory, where it is specially treated and then examined under the microscope. Special stains are used to look for the characteristic antigens in the biopsy specimen in order to confirm the diagnosis. Other tests that some people might have include a chest X-ray, computed tomography (CT scan) and a bone marrow biopsy, but these are not always done routinely.
Healthy blood cells CLL is usually diagnosed by looking at the cells in your blood; the disease is suspected when the blood contains too many white cells called lymphocytes.
CLL-affected blood cells
CLL cells have a distinctive appearance when viewed through a microscope. They are small cells with condensed chromatin (which is found in the central nucleus of the cell) and very little cytoplasm (the part of the cell between the nucleus and the cell wall). One of the hallmarks of CLL is so-called 'smear' or 'smudge' cells, which are CLL cells that have been squashed during the making of the blood film.
CLL cells under the microscope
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Stages of CLL After being examined and having tests your CLL will be described as being at a certain ‘stage’. This helps doctors decide when and how to treat the CLL. The staging system that is most commonly used in the UK – the Binet staging system – takes into account how many groups of lymph nodes are enlarged (most commonly the groups in the neck, the armpit or groin) and your blood counts: Stage A
Fewer than three groups of enlarged lymph nodes can be felt by your doctor
Stage B
Three or more groups of enlarged lymph nodes can be felt by your doctor
Stage C
There are reduced numbers of red blood cells and/or platelets in your blood, irrespective of how many groups of enlarged lymph nodes your doctor can feel
How will CLL affect me? As with other types of low-grade non-Hodgkin lymphoma, people with CLL tend to experience repeated remissions and relapses. This means that it flares up from time to time, with periods of inactivity in between. The behaviour of CLL varies widely from person to person. In some people the disease goes on for decades without requiring any treatment. Other people have a more aggressive form of the disease and will need treatment early on. As mentioned on page 2, in a few people (about 1 in 10) their CLL can eventually start to change form and grow more quickly. It can either change into a type of leukaemia – B-cell prolymphocytic leukaemia – in which the malignant cells appear much larger under the microscope than the classic CLL cells – or into a type of lymphoma called diffuse large B-cell lymphoma (when this happens it is known as Richter syndrome). This kind of change is called transformation. If this happens your treatment will change and you will receive the type of treatment normally used for these faster-growing conditions.
Prognostic factors It is not possible to predict exactly how CLL will affect you over time, but there are a number of things that give the doctors an indication of how your disease might behave. These are called ‘prognostic factors’ and they include: ●
the stage of your CLL (see above)
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whether or not your blood tests show low counts of red blood cells and platelets
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whether or not you have particularly swollen lymph nodes
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how quickly the numbers of abnormal CLL cells in the blood are increasing
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what changes have happened to the chromosomes and genes of the abnormal lymphocytes.
The medical team will take all these factors into account when they make decisions about how best to treat you.
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What is the treatment for CLL? Although treatments can be very effective, it is important to appreciate that classic CLL is not curable with standard treatments – the only potentially curative treatment is allogeneic stem cell transplantation (transplanting stem cells from a donor), though this is an intense and complicated procedure (see page 10). There are four basic questions to address: ●
when to start treatment
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what treatment to have
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when to stop treatment
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what to do next.
When to start treatment In general, treatment is only necessary if the CLL is: ●
causing symptoms such as profuse sweating
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causing complications such as bone marrow failure
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progressing so quickly that complications look imminent.
There is currently no evidence that treating people who have no symptoms and only a few enlarged lymph nodes does any good, although trials are beginning to re-examine this question in people with early disease who are considered to be at particular risk of their disease progressing. In the absence of one of these clear reasons to treat the CLL, your doctors will not start to treat the underlying CLL itself but would treat any autoimmune complications that you might have (for example AIHA or ITP). Apart from this you will be carefully monitored with regular check-ups to assess the activity of the CLL. This type of active monitoring is often called watch and wait. This can be a difficult period to go through because you might feel that ‘nothing is being done’, but research has shown it to be the best approach in some people.
What treatment to have? The aim of treatment in CLL is to improve symptoms and put the disease into a remission. This requires measures to reduce the number of abnormal CLL cells in the body. There are three types of drugs that are currently available: chemotherapy, antibody therapy and steroids.
Chemotherapy Chemotherapy (drugs that damage or kill cancer cells) remains the cornerstone of initial therapy and the main choices are: ●
a combination of rituximab, fludarabine and cyclophosphamide (R-FC)
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chlorambucil
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bendamustine.
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R-FC is the treatment of choice for most fit people with CLL because it has been shown to result in improved survival. Treatment is given every month for up to six cycles. The rituximab (which is actually an antibody therapy rather than a chemotherapy drug, see below) is given into the vein over several hours on the first day of each treatment. The first dose of rituximab may be split over 2 days if the number of CLL cells in the bloodstream is above a certain level. The fludarabine and cyclophosphamide are given by mouth over 3–5 days. R-FC is very effective, but about a quarter of people who have this treatment develop an infection and it can cause prolonged lowering of the numbers of healthy blood cells in some people, so it is carefully monitored. It should not be given to anyone with severe kidney impairment. The possible benefit of adding another chemotherapy drug, mitoxantrone, to R-FC (R-FCM) is currently being examined in clinical trials (the ARCTIC and ADMIRE trials, see http:// cancerhelp.cancerresearchuk.org.trials/), and there may be occasions when R-FCM might be recommended even if you are not on one of these trials. Chlorambucil is given as tablets, usually for 7 days every month for 6–12 months. This drug works well in some people, especially people with a milder form of the disease, and is generally well tolerated. Bendamustine has recently been approved by the National Institute for Health and Clinical Excellence (NICE) as an initial treatment for people with stage B or C disease who cannot have fludarabine (the ‘F’ in R-FC). The drug is given into the vein over two consecutive days, and this is repeated every month for up to six cycles. Doctors are still researching the best ways of using bendamustine in CLL. Rituximab combined with bendamustine (R-B), might be a useful treatment in people who are less fit and who relapse early after being treated with chlorambucil or in fitter people who cannot have R-FC because of kidney problems. R-B has not yet been officially approved by NICE in these situations, however, and so at the time of writing this article its availability varies from region to region.
Antibody therapy Antibodies are a form of biological therapy. Biological therapies use substances similar to those produced naturally by the immune system but which are made in a laboratory. Antibodies are proteins made by the immune system to fight infection. Antibodies used in the treatment of cancer have been specially manufactured to attach themselves to tumour cells. Tumour cells coated with these antibodies are then attacked and destroyed by your immune system. Rituximab is the most commonly used antibody in CLL. Clinical trials have shown that adding rituximab to fludarabine-cyclophosphamide chemotherapy (R-FC) approximately doubles the chance of achieving a complete remission, lengthens remissions and prolongs survival. The R-FC combination lowers the numbers of healthy white cells more than FC alone but this does not seem to translate into an increased risk of infection. R-FC is approved by NICE for people with previously untreated CLL who are considered fit enough to tolerate the side effects and who would previously have received FC alone. NICE has also approved the use of R-FC in people with relapsed CLL provided they are not known to be resistant to fludarabine and have not received rituximab previously. Chronic lymphocytic leukaemia
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Another antibody used in the treatment of CLL is alemtuzumab (often called by its trade names, MabCampath® or Campath®). Campath can be very effective at clearing CLL cells from the blood and bone marrow but it is not so good at shrinking down very large lymph nodes. It is usually reserved for people in whom fludarabine-based chemotherapy has not been effective or who have a defect in a gene called TP53. Campath is administered three times a week for up to 3–4 months and it can be given into a vein or under the skin. When given into a vein its main side effect is flu-like symptoms. When given under the skin, it can cause a local skin reaction. The main limitation of Campath is that it also knocks out important cells called T cells, which protect us against viruses. Most people harbour a virus called cytomegalovirus (CMV for short) and this virus does not cause any problems if there are plenty of T cells around to keep it under control. When you are being treated with Campath, however, the CMV virus can become active and cause a variety of problems. For this reason, if you are on Campath treatment you should have weekly blood tests to look for CMV activity. If the virus is detected, early treatment is given and the infection almost always settles down. Campath has not been assessed by NICE but is available in many parts of England through a funding body called the Cancer Drugs Fund. Macmillan Cancer Support has produced a useful booklet on the Cancer Drugs Fund (contact details on page 12). A third antibody called ofatumumab has also been shown to be effective in people with CLL who have relapsed after having Campath. It is not currently NICE-approved but it might be available in some areas through the Cancer Drugs Fund. The RIAltO trial for less fit patients began in December 2011 and is comparing ofatumumab plus chlorambucil with ofatumumab plus bendamustine. The CLL210 trial for people with TP53 gene defects or for people who do not respond to R-FC treatment within 12 months is investigating the combination of Campath with the steroid dexamethasone and a drug called lenalidomide. Lenalidomide is a new drug that mainly works by enhancing the action of antibodies and it has been shown to have an effect in CLL. At present it is not licensed for this condition, however, and so is usually only available in clinical trials.
Steroids Steroids are useful drugs in CLL. They are used in three different situations: ● ●
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to treat autoimmune complications (AIHA and ITP) to improve blood counts in people who have bone marrow failure before starting chemotherapy (because chemotherapy can make the bone marrow failure worse in the short term) as an alternative to Campath in people who do not respond to fludarabine-based chemotherapy – although this usually requires big doses of steroids.
There is some evidence showing that it might be useful to add steroids to rituximab or to Campath. Steroid-Campath combinations may be particularly useful for people who have forms of CLL that are difficult to treat, for example if you have particularly enlarged lymph nodes. Another form of CLL that can be difficult to treat is when the TP53 gene is found to be missing. If the TP53 gene is missing the cells don’t produce a very useful protein called p53 that helps chemotherapy to work and generally keeps cancer cells in check. Chronic lymphocytic leukaemia
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A steroid-Campath combination can be used for people in this situation too. The steroids have to be given in fairly high doses in this type of combination treatment, however, and there is a significant risk of infection and other side effects. This treatment should therefore be closely supervised by a specialist centre.
Other treatments for CLL/SLL Occasionally, there may be a role for radiotherapy, for example in early-stage SLL; or in CLL if you have a particularly troublesome lymph node that has not responded to drug treatment; or if drug treatment is not considered appropriate. In addition, a few people need to have their spleen removed – an operation called a splenectomy. The usual reason for considering a splenectomy in CLL is troublesome AIHA or ITP rather than the CLL itself. There are a lot of exciting new treatments that are currently under evaluation. These include the antibody GA101, which attaches itself to the same protein as rituximab (the CD20 antigen), and Btk inhibitors and P13 kinase inhibitors, which are small-molecule drugs. Small-molecule drugs are drugs that are small enough to enter into the malignant cells and interfere with important cell processes such as those involved in cell growth.
When should I stop treatment? Each chemotherapy treatment will have a recommended maximum duration. For example, R-FC and bendamustine are usually given for up to 6 months, chlorambucil for 6–12 months and Campath for 3–4 months. Your treatment may be stopped early if you are experiencing severe side effects or if it does not seem to be working. If your treatment is not working, your consultant might suggest a different one.
Taking part in clinical trials Clinical trials are very important because they allow new treatments to be evaluated and compared with more established ones and we have mentioned several of the current trials in the section on treatments. If you decide to take part in a trial you can be assured that you will be receiving modern treatments that are entirely appropriate for your current situation, whether you receive a new treatment or the currently accepted standard treatment. You do not need to take part in a clinical trial if you don’t want to, however, and you can be similarly assured that you will be given the best currently available treatment for your CLL.
Supportive treatments in CLL Supportive treatments are treatments that help with the symptoms of CLL or with the side effects of the drug treatments you are having for the CLL. For example, supportive treatments can be given for: ●
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Infections – you might be given continuous antibiotics to try and prevent infections and if you do develop an infection it will need to be treated promptly with the most suitable antibiotic. Low counts of red blood cells or platelets – due to bone marrow failure. Some people will require transfusions of donor red blood cells and/or platelets. These should be irradiated to get rid of donor T cells that could induce graft-versus-host disease (see the section on transplantation on page 10).
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L ow antibody levels – this might be treated with immunoglobulin replacement therapy. This can be regarded as a special type of blood transfusion in which you are transfused with antibodies from blood donors. This can be a useful treatment if you have problems with recurring infections due to the CLL. AIHA and ITP – these autoimmune complications are treated with steroids initially and sometimes with transfusions of red blood cells or platelets from a donor.
What happens next? Most people will go back to a watch and wait approach after a course of treatment. This means that you will have regular check-ups and your consultant will monitor your situation. At some stage the disease is likely to flare up again and further treatment will be necessary. Depending on what the first treatment was and on how well it worked, it can be repeated. Because no treatment works quite as well or for as long a time the second time around, however, sooner or later you will probably need different and possibly stronger treatments. As an alternative to going back to watch and wait, some people who go into a good remission might be considered for a bone marrow or stem cell transplant.
Stem cell transplants Stem cells are immature cells that have the potential to turn into healthy mature blood cells. There are two types of stem cell transplants: autologous, in which one’s own stem cells are used; and allogeneic, in which someone else’s stem cells are used. Both types of transplant are likely to keep the CLL in remission for longer than it would have been if you didn’t have a transplant. Indeed, allogeneic transplantation is curative in some people. However, transplantation is a complicated procedure and is also associated with significant risks, which mean that the procedure can sometimes end up doing more harm than good. Autologous transplantation involves giving very big doses of chemotherapy or radiotherapy to kill off as many CLL cells as possible. Your stem cells are collected first (this is called ‘harvesting’) in a procedure that is like giving blood, and then you are given high doses of chemotherapy before your stem cells are given back into your bloodstream. In this way, your blood counts recover within 2–3 weeks and you are protected from long-term suppression of the bone marrow. This is the less risky of the two types of transplant, but the procedure nevertheless entails up to a month in hospital and several further months at home recovering. Furthermore, many people with CLL are unable to go ahead with an autologous transplant because insufficient numbers of stem cells are collected during the harvesting stage. For these reasons, together with the advent of newer treatments, autologous transplantation is used less frequently now in the treatment of CLL. Allogeneic transplantation seems superficially similar to autologous transplantation but in fact it is very different because it involves replacing your immune system with someone else’s (the immune system is passed on with the donor’s stem cells). The idea is that the donor immune system fights the CLL in a way that your own immune system is unable to do. The main problem with this procedure is that the donor immune system also fights your own healthy cells. This is called graft-versus-host disease and needs to be prevented with tablets Chronic lymphocytic leukaemia
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that suppress your immune system until the donor immune cells learn not to attack your body. Unfortunately, having these tablets can make you more prone to developing infections. Allogeneic transplantation is significantly more risky than an autologous transplant, and full recovery can take much longer. Because it is such a challenging and risky treatment, it is usually reserved for relatively young, fit people whose CLL has a high risk of getting worse – for example people whose TP53 gene is defective or people who do not respond well to R-FC treatment. In addition to the question of whether or not to have a transplant, there is also the question of when to have it. The danger in waiting too long is that it might not be possible to achieve the sort of remission that is required for a transplant to stand the best chance of working well. On the other hand, transplanting too early can expose people to unnecessary risks from the procedure itself. At the end of the day, a transplant, particularly an allogeneic transplant, is a situation in which short-term risks have to be traded off against potential, but often very uncertain, long-term gains.
Other later treatments Another possible way of making remissions last longer is to give additional drug treatment, for example Campath or lenalidomide. This is called ‘consolidation’ or ‘maintenance’ therapy. This approach is currently being examined in clinical trials (Campath in the CLARET trial; lenalidomide in the CONTINUUM trial) and therefore should still be regarded as experimental.
Conclusions CLL is now acknowledged to be a highly complex and variable disease. Much has been learned about its biology over the last 10–15 years, and significant progress has been made in its treatment. These developments have also made the treatment of CLL more complicated. Although the subject can appear confusing, things can be simplified by thinking about each of the key treatment questions as they arise (when to start, what to have, when to stop, what to do next). A good piece of advice whenever there is a decision to be made about treatment is to make a list of the available options, together with their pros and cons, and to discuss these with your medical team. If you are having your treatment within the framework of a clinical trial the decision is often made for you within the guidelines of the trial protocol. Finally, it is important for people with CLL to build up a good relationship with their haematologist and specialist nurse. For most people, CLL is a lifelong disease and much support and advice will be required along the way. Most haematologists will be happy to answer questions, discuss treatment options or refer you on to a colleague with a special interest in CLL if there are any difficult or unusual issues that need to be addressed.
Acknowledgement The Lymphoma Association is grateful to Professor Andrew Pettitt, consultant haematologist at the Royal Liverpool University Hospital and Chairman of the UK CLL Forum, for writing this article.
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More information The Lymphoma Association produces a wide range of booklets and information sheets on all aspects of lymphoma, including the tests and investigations that are involved, the treatments that are available and what is involved in taking part in clinical trials. We also have information on how to cope with the practical and emotional difficulties of living with an illness that can extend over many years. Visit our website at www.lymphomas.org.uk or phone our freephone helpline on 0808 808 5555 if you would like to receive any of this information or if you would like to talk to someone about your CLL.
Feedback We continually strive to improve our information resources for people affected by lymphoma and we would be interested in any feedback you might have on this article. Please visit www.lymphomas.org.uk/feedback or email
[email protected] if you have any comments you would like to make. Alternatively, please phone our helpline on 0800 808 5555.
Useful organisations CLL Support Association c/o 39–40 Eagle Street London. WC1R 4TH 0800 977 4396 via website www.cllsupport.org.uk
CancerHelp UK 0808 800 4040 (Monday–Friday, 9am–5pm) via website www.cancerhelp.cancerresearch.org.uk
Leukaemia & Lymphoma Research 39–40 Eagle Street London WC1R 4TH 020 7405 0101 (Monday–Friday, 9am–5pm)
[email protected] www.leukaemialymphomaresearch.org.uk
Macmillan Cancer Support 89 Albert Embankment London SE1 7UQ 0808 808 00 00 (Monday–Friday, 9am–8pm) Order line for booklets (including Cancer Drugs Fund) 0800 500 800 via website www.macmillan.co.uk
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Selected references The full list of references is available on request. Please contact us via email (
[email protected]) or telephone 01296 619409 if you would like a copy. Cramer P, Hallek M. Prognostic factors in chronic lymphocytic leukemia – what do we need to know? Nature Reviews Clinical Oncology, 2011. 8: 38–47. Hallek M. Chronic lymphocytic leukemia for the clinician. Annals of Oncology, 2011. 22 (Suppl 4): iv54–iv56. Gribben JG. How I treat CLL upfront. Blood, 2010. 115: 187–197. Hallek M, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase III trial. Lancet, 2010. 376: 1164–1174. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood, 2008. 111: 5446–5456. Pettitt AR. Glucocorticoid-based combination therapy for chronic lymphocytic leukemia: new tricks for an old dog. Leukemia and Lymphoma, 2008. 49: 1843–1845. Dreger P, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia, 2007. 21: 12–17.
We make every effort to ensure that the information we provide is accurate but it should not be relied upon to reflect the current state of medical research, which is constantly changing. If you are concerned about your health, you should consult your doctor. The Lymphoma Association cannot accept liability for any loss or damage resulting from any inaccuracy in this information or third party information such as information on websites which we link to. Please see our website (www.lymphomas.org.uk) for more information about how we produce our information. © Lymphoma Association PO Box 386, Aylesbury, Bucks, HP20 2GA Registered charity no 1068395 Produced 03.02.2012 Next revision due 03.02.2014
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