Professor Andrew Pettitt is Consultant Haematologist at the Royal Liverpool University Hospital.

November 2006

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Introduction
CLL is really a type of so-called indolent, or slowly growing, B-cell non-Hodgkin’s lymphoma (NHL). It is called a leukaemia because it almost always involves the blood. Problems arise when the malignant cells accumulate to the point at which they stop the immune system or bone marrow from working properly or when lymph nodes become so enlarged that they start to press on important structures. Like other types of indolent B-cell NHL, CLL is not curable except with a bone marrow or stem-cell transplant from another individual. This is a risky proposition that can be difficult to justify in a disease with a natural history that can often be measured in decades. So, for most patients, treatment is aimed at alleviating symptoms and preventing life-threatening complications.

Basic considerations
There are four basic questions in relation to treating CLL: when to start, what to give, when to stop and what to do next. The answers to these questions are likely to vary depending on whether one is dealing with a gentle or more aggressive type of CLL, and also on patient age and fitness. For example, in an elderly person with relatively benign form of CLL and other medical problems, a ‘softy, softly’ approach would be appropriate. At the other end of the spectrum, a fit young patient with a malignant form of CLL might benefit from more aggressive treatment.

Consideration needs to be given not only to initial treatment but also what to do when the disease relapses. In general, the more the disease comes back, the less well it responds to further therapy. If relapse occurs after a reasonably long time interval, say more than two years or so, it is reasonable to give the same treatment again if it was well tolerated the first time round. This particularly applies to more gentle treatments such as chlorambucil (see below). If, on the other hand, the disease comes back early after initial therapy or does not respond, different and probably stronger second-line treatment is indicated.

When to start?
It is self-evident that treatment is likely to benefit patients with CLL-related symptoms (e.g. tiredness, sweats and weight loss) or those with imminent complications due to a high tumour burden. It is very likely that treating such patients extends their life span life but this has never been proved. To do so would be unethical, as it would require a clinical trial in which some patients requiring treatment would be denied it. There is, however, good evidence that treating asymptomatic patients who have a low tumour burden with gentle chemotherapy in the form of chlorambucil (see below) is of no benefit. So the current wisdom is that treatment should be reserved for patients with CLL-related symptoms or imminent complications. Other indications for treatment are more controversial. Some authorities recommend starting treatment when lymph nodes become enlarged for the first time,or when the red cells or platelets fall below a given level, or when the number of CLL cells in the blood exceeds a given level or increases faster than a given rate. Others advocate a more conservative approach. As this is an area where there are no absolute rights and wrongs, patient preference is also very important and needs to be taken into account.

Clinical trials are currently addressing the ‘when to start’ question in patients with a low tumour burden in a more sophisticated way by focussing on those patients who are at a high risk of early progression as determined by ‘biological prognostic factors’ (prognostic factors) and by using treatments that are more effective than chlorambucil, such as alemtuzumab (Campath). Entry into such trials is to be encouraged, but outside such trials the usual rules should apply.

What to give?
Chlorambucil. Gentle chemotherapy in the form of chlorambucil tablets has, for many years, been the mainstay of first-line treatment. Chlorambucil is a member of a class of drugs called alkylating agents. These drugs work primarily by damaging the DNA of tumour cells. This in turn triggers a process called apoptosis in which the tumour cells commit suicide. The effectiveness of chlorambucil, like other types of chemotherapy depends on the dose used, i.e. the bigger the dose, the better it works. However, bigger doses also mean more side effects. There are many different ways of giving chlorambucil, but nowadays most doctors in the UK give it for 7 days every month for 6 to 12 months, this being the regimen used in the pivotal UK CLL4 trial (CLL trials in the UK). About two thirds of patients respond to treatment but relatively few patients enter a so-called complete remission. The latter means that the disease can no longer be detected by conventional methods. However, it does not amount to a cure, as there will always be some CLL cells left behind that will eventually grow back. The average time for this to happen is about two years. Clinical trials have shown that the effectiveness of chlorambucil is not improved by adding in other drugs such as steroids or other types of chemotherapy.

Side effects due to chlorambucil are usually mild. Data from the UK CLL4 trial show that approximately one third of patients develop nausea but this is rarely severe. In addition, about one quarter of patients require hospital admission at some stage due to infection. Other side effects, including hair loss, are quite rare.

Fludarabine. This is a relatively new member of a class of drugs called purine analogues. These agents also damage tumour-cell DNA but do so indirectly by interfering with DNA repair processes. Fludarabine is usually given by mouth 5 days every month for up to 6 months. Fludarabine is more effective than relatively low doses of chlorambucil However, in the UK CLL4 trial, which used a higher dose of chlorambucil, fludarabine was only marginally more effective. The benefit of fludarabine over chlorambucil is however, offset by a higher frequency of side effects. So in the final analysis and taking into account the doses used, fludarabine is probably not much better than chlorambucil.

One of the most notorious side effects of fludarabine is so-called auto-immune haemolytic anaemia (AIHA), a process in which the immune system attacks the red blood cells resulting in anaemia and jaundice (yellow discolouration of the skin and eyes). AIHA can occur spontaneously in CLL but may also be triggered by therapy. In fact, therapy-induced AIHA is no more common after fludarabine than after chlorambucil. However, fludarabine-induced AIHA is more likely to be severe and in some cases can be life-threatening. Fludarabine should not be given to patients who have experienced a previous episode of fludarabine-induced AIHA.

In addition to AIHA, the other main issue with fludarabine is that the drug is excreted from the body predominantly through the kidneys. Therefore, patients with malfunctioning kidneys can end up with what amounts to an over-dose. It is therefore of paramount importance that kidney function is checked out thoroughly before starting treatment with fludarabine. If the kidney function is only mildly impaired, half the usual dose can be used. However, patients with severe kidney impairment should not receive the drug at all.

Fludarabine suppresses the immune system, and patients receiving the drug, either alone or in combination with other drugs, should probably take an antibiotic called co-trimoxazole (Septrin) to reduce the risk of a special type of pneumonia called PCP.

Fludarabine plus cyclophosphamide (FC). Laboratory data indicate that fludarabine can act in concert with certain alkylating agents to kill CLL cells. In keeping with this, several clinical trials of first-line therapy, including the UK CLL4 trial, have shown that fludarabine used together with an alkylating agent called cyclophosphamide (a regimen known as ‘FC’) is significantly more effective than either chlorambucil or fludarabine on its own. FC is usually given by mouth for 5 days every month for up to 6 months. There is twice as much chance of achieving a complete remission with FC than with chlorambucil or fludarabine, and remissions last about twice as long. As might be expected, FC also has more side effects but the benefits seem to outweigh the risks, at least for patients who are reasonably fit. The UK CLL4 trial showed that the benefits of FC extended across all age groups, including patients above the age of 70. Interestingly, AIHA is less common after FC than after chlorambucil or fludarabine on its own. Based on all these considerations, many authorities, including those overseas, argue that FC should be the new Gold-Standard first-line therapy for those patients who are fit enough to receive it.

Despite the superiority of FC over chlorambucil or fludarabine in terms of inducing longer lasting remissions, clinical trials have failed to show that FC prolongs life. This is probably because patients who receive chlorambucil or fludarabine as initial treatment usually go on to benefit from FC as second-line therapy when they relapse, or if they do not respond. This is an example of the so-called ‘cross-over effect’ that prevents clinical trials from proving that new treatments prolong life.

One concern that has been raised about stronger types of chemotherapy is their potential to damage the DNA of normal tissues and thereby increase the risk of second cancers. For example, some reports claim that patients who have received fludarabine-based chemotherapy have an increased risk of developing a condition called myelodyspastic syndrome or ‘MDS’. MDS is an abnormality of the bone marrow that results in low blood counts and can turn into a serious and aggressive form of leukaemia called acute myeloid leukaemia or ‘AML’. There is no evidence as yet from the big clinical trials that this is a major problem but this could be because patients in these trials have not been followed up for long enough. Despite these concerns, it should be stressed that for most patients requiring treatment for CLL, the benefits of more effective treatments such as FC are likely to outweigh any risks. Besides which, most patients will probably end up receiving FC at some stage during their disease.

Other types of chemotherapy. Many other types of chemotherapy regimens have been used successfully in CLL. However, it is unlikely that any of them is any better than FC. Special mention should be made of a regimen called CHOP, which has reasonable activity in patients who are refractory to fludarabine. The one clear indication for CHOP is when CLL turns into an aggressive lymphoma called diffuse large B-cell lymphoma (DLBCL). This is called a Richter’s transformation. Nowadays most people would use CHOP in combination with rituximab (see below), as this regimen is now the standard treatment for DLBCL occurring de novo.

Rituximab (Mabthera). Rituximab is a so-called ‘monoclonal antibody’ that binds to a structure called CD20 on the surface of B cells (including CLL cells) leading to their destruction by the immune system. Compared with chemotherapy, rituximab has relatively few side effects apart from flu-like symptoms while the antibody is being given into the vein. In other types of B-cell NHL, rituximab has been proved to increase the effectiveness of chemotherapy without adding significantly to the side effects. We do not yet know whether the same is true in CLL but two clinical trials are addressing this question, one in the first-line setting and one in previously treated patients (CLL trials in the UK). Both trials are comparing FC with FCR. Available information suggests that FCR is very effective but there is as yet no proof that it is better than FC without rituximab.

Alemtuzumab (MabCampath). Alemtuzumab is another antibody treatment that is known to be highly effective in CLL. It is usually given as an intravenous infusion over 2 hours three times a week for three or four months. Like rituximab, it can cause flu-like symptoms while it being administered. To reduce these side effects, paracetamol and antihistamines are given prior to each infusion. Alemtuzumab can also be given as an injection under the skin, and trials are in progress to confirm that the drug is as effective and safe when given in this way. Available data suggest that alemtuzumab has fewer side effects when given under the skin but takes a little longer to work. Very importantly, alemtuzumab is active in cases of CLL that have a p53 deletion or mutation. Patients with this type of CLL usually respond very poorly to chemotherapy (prognostic factors).

At the moment, alemtuzumab is licensed for use in patients who relapse after, or do not respond to, fludarabine. Depending on the exact circumstances, about 50% of patients in this category can expect a useful response. Alemtuzumab is good at clearing out blood and bone marrow but not so good at shrinking down enlarged lymph nodes. Patients with lymph nodes bigger than 5cm have a particularly poor response.

The main problem with alemtuzumab is that it temporarily depletes the body of cells called T cells, which are important for fighting viruses. This can result in the so-called ‘reactivation’ of viruses that are normally kept in check by the immune system. The most notorious of these is cytomegalovirus, or ‘CMV’. CMV reactivation can be asymptomatic or result in a fever or symptoms such as breathlessness or diarrhoea, depending on which part of the body is affected. Patients receiving alemtuzumab should be monitored for CMV reactivation with a weekly blood test and started on appropriate treatment if reactivation is detected. Alemtuzumab does not necessarily need to be stopped if there are no symptoms or fever. As with fludarabine and FC, patients receiving alemtuzumab should also take co-trimoxazole to reduce the risk of PCP.

Steroids. Steroids used in the treatment of CLL are called ‘glucocorticoids’ and have nothing to do with the steroids that some body-builders take. Steroids have three main uses in CLL: (1) treating auto-immune complications such as AIHA and ITP (immune thrombocytopenic purpura, i.e. low platelets due to destruction by the immune system); (2) improving the bone marrow function prior to chemotherapy in patients presenting with very low blood counts due to heavy bone marrow infiltration with CLL; and (3) treating patients with disease that has not responded well to chemotherapy. (1) and (2) usually involve modest daily doses of a steroid tablet called prednisolone, whereas (3) involves high-dose methylprednisolone (HDMP), which is usually given intravenously for 5 consecutive days every month. Like alemtuzumab, HDMP is active in cases of CLL with p53 abnormalities.

HDMP given in combination with alemtuzumab may be more effective than either agent on its own but is experimental and needs to be used with extreme caution owing to its potential for serious side effects (visit http://www.clltopics.org/PhysCor/SteroidCampath.htm for more details). The regimen is currently being evaluated in the UK CLL206 trial, which is specifically for patients with a p53 deletion (CLL trials in the UK).

Side effects of steroids include stomach irritation, mood swings, sleeplessness, loss of muscle, redistribution of body fat, thinning of the skin and bones, fluid retention, high blood pressure, diabetes and cataracts. Patients on long-term continuous steroids are probably particularly prone to long-term side effects such as osteoporosis and should therefore receive concomitant therapy with calcium and vitamin D supplements, possibly also together with an appropriate bisphosphonate drug. The latter reduce the risk of osteoporosis but can results in a serious dental problem called ‘osteonecrosis of the jaw’. Some authorities also recommend that patients on steroid therapy should also receive a drug to neutralise stomach acid to reduce the risk of stomach ulcers.

Infection is another important complication of steroids, and patients receiving high-dose steroid therapy should receive preventative antibiotics including co-trimoxazole to prevent PCP. Thrush can also be a particular problem, along with shingles, and some authorities advocate the use of pre-emptive anti-fungal and anti-viral drugs in patients receiving high-dose or long-term steroid therapy.

New drugs. Many different agents are currently being evaluated for their activity in CLL. However, until the results of these studies are available, it is difficult to justify their routine use.

When to stop?
Nobody knows how much treatment of a given type is best. However, it is conventional to give 6 to 12 months of chlorambucil, up to 6 cycles of fludarabine or FC, and up to 3 or 4 months of alemtuzumab. Treatment should be discontinued if it is clearly not working any more or if side effects are intolerable or life threatening.

What to do next?
This is the most difficult bit. Conventional wisdom based on the available data is to resume a watch and wait approach when treatment has finished. However, we know that patients who achieve really good remissions tend to stay in remission longer than patients who achieve less impressive remissions. It therefore tempting to speculate that further treatment of patients who are already in a good remission might achieve still better results. Such treatment is referred to as ‘consolidation therapy’. There are currently three forms of treatment that fall into this category: so-called ‘maintenance therapy’ with alemtuzumab, autologous stem-cell transplantation (‘autografting’), and allogeneic stem-cell transplantation (‘allografting’). All treatments are associated with potentially serious and, indeed, life threatening complications. It is therefore of paramount importance to weigh up their pros and cons very carefully.

Alemtuzumab maintenance. This is still at the experimental stage and should not be considered outside clinical trials. However, there is some evidence to suggest that it may be effective in delaying relapse. On the other hand it can also result in serious infections if given too soon after successful chemotherapy. Another approach that will investigated in future clinical trials is to monitor patients very carefully for the earliest evidence of progression and when progression occurs to give a short course of alemtuzumab to settle the disease down before it causes any symptoms or complications. However, this approach is, as yet, entirely unproven.

Autologous stem-cell transplantation. An autograft consists of delivering a really big dose of chemotherapy either alone or in combination with total body radiation. The idea is to kill as many tumour cells as possible in one go. If that was all that happened, permanent bone marrow failure would result, and this would be fatal. To get around this problem, bone marrow or stem cells can be removed from the body before the big dose of chemotherapy and given back like a blood transfusion afterwards. The stem cells find their way back to the bone marrow and start to make healthy blood cells.

In practice the procedure is in two parts. The first step is to get hold of the stem cells. This can be done either by taking them directly from the bone marrow but this requires a general anaesthetic. Alternatively, the bone marrow stem cells can be persuaded to enter the bloodstream where they can be scooped off using a machine called a cell separator, which is similar to a dialysis machine. To get stem cells to enter the blood stream it is necessary to give a dose of chemotherapy (usually a fairly large dose of cyclosphamide given intravenously) and then start daily infections of a growth factor called G-CSF. After 7-10 days, stem cells appear in the blood stream and can then be harvested using the cell separator machine.

The transplant proper involves up to a month in hospital and can be quite unpleasant. The worst side effect is called ‘mucositis’. The means that the lining of the mouth, gullet and bowel becomes very inflamed and sore. The other main problem is infection. Despite this, it is a relatively safe procedure. The most serious long-term complication is MDS.

Patients who receive autologous transplants seem to do quite well in general but most eventually relapse, so it is probably wrong to think of it as a curative procedure. Instead, it should be thought of as a way of setting the clock back. The favourable outcome seen after autografting may be due in part to patient selection, i.e. patients with disease that is difficult to treat may never be in a fit enough state for transplantation. The MRC CLL5 trial is looking at whether it is better to have an autograft early during the course of the disease or at a later stage.

Allogeneic stem-cell transplantation. Allogafting is similar to autografting but differs in that, instead of collecting and re-infusing the patient’s own stem cells, someone else’s stem cells and immune system are infused. Brother or sister donors are preferred, and there is a 1 in 4 chance that any one sibling will be a match. For those patients without a family donor, there is a fair chance of finding an unrelated donor from one of the large panels. This has the theoretical benefit that the donor immune system can potentially recognise any left over tumour cells as foreign and pick them off. On the other hand, the donor immune system may also recognise the recipient’s normal cells as foreign, a situation that can result in so-called ‘graft-versus-host disease’ (GVHD). GVHD can be serious and, indeed, life threatening and needs preventing with powerful immuno-suppressive drugs for 4-6 months post transplant. This is roughly how long it takes for the donor and recipient cells to get used to each other, but sometimes complications and side effects can rumble on for a year or more. While the immune system is suppressed, patients are highly susceptible to infections and reactivation of viruses such as CMV. So the main disadvantage of an allograft compared to an autograft is that it is significantly more unpleasant and risky due to GVHD and infection. On the other hand, it has the potential to be curative.

New and safer ways of doing allografts have been developed that involve relatively low doses of chemotherapy. This is referred to as ‘reduced intensity conditioning’ or RIC allografting or a ‘mini-allo’. However, even a RIC allograft is associated with significant risks. The main difficulty when thinking about allografting is to weigh the risks and side effects of the procedure against the potential benefits. At the end of the day, allografting amounts to a big gamble in which short-term risks are traded off against potential long-term gains. The dilemma is not only one of whether or not to have an allograft, but also when to have one. Thus, transplants consistently achieve the best results in patients who have not received too much in the way of previous treatment and are in remission at the time of transplantation. On the other hand,allografting has the potential to shorten as well as prolong life. This is very much an area where there are no clear answers, and under these circumstances patient choice is of paramount importance.

The future
When it comes to the treatment of CLL there are clearly many more questions than answers. This statement has two main implications: (1) clinical trials are needed to answer these various questions, and (2) outside trials patient preference is of paramount importance in making treatment decisions, especially those where the stakes are high. In the future, it is likely that treatment decisions will be made easier due to the advent of biological prognostic factors but there is currently no evidence that knowledge of prognostic factors influences the outcome in any way.

Obtaining this evidence is one of the priorities for future clinical trials. It may take another 5 or 10 years, but it is likely that we will eventually see the disappearance of a ‘one-size-fits-all’ approach to therapy and instead see the emergence of individualised therapy tailored to disease biology in terms of when to start, what to give, when to stop and what to do next. However, we can only get to this point by developing and supporting clinical trials that address important questions. The international CLL scientific community is striving to develop such trials but it is ultimately local haematologists and patients who bring them to fruition.

So at the end of the day, to take forward the treatment of CLL requires a three-way partnership between scientists, doctors and patients. We are fortunate in the UK to have an institution whose precise purpose is to facilitate such a partnership. The institution is the UK CLL Forum and the person who founded it six years ago is Professor Terry Hamblin. Terry is stepping down as chairman this year (2006) and we all owe him a great debt of gratitude for putting in place the collaborative infrastructure that will hopefully ensure that the UK will remain at the cutting edge of CLL research for the foreseeable future. 

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