Treatment of CLL
By Professor Andy Pettitt, Consultant Haematologist, Royal Liverpool University Hospital
updated 2012 by Dr Anna Schuh, Consultant Haematologist, Oxford University Hospitals
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 when lymph nodes become so enlarged that they start to press on important structures or when patients get constitutional symptoms such as night sweats, weight loss or loss of appetite. 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.
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.
A clinical trial led by the German CLL Study Group currently addresses 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’ (see Prognostic Factors article on CLLSA website ) and by using FCR treatment that is more effective than chlorambucil, Entry into this trial is to be encouraged, but outside trial 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 (see CLL trials in the UK article on CLLSA website). About two thirds of patients respond to treatment but very 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, cyclophosphamide and rituximab (FCR)
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, single agent fludarabine was only marginally more effective. The benefit of fludarabine over chlorambucil is however, offset by a higher frequency of side effects, especially autoimmune haemolytic anaemia (AIHA). So in the final analysis and taking into account the doses used, fludarabine on its own is probably not much better than chlorambucil and therefore no longer used as a single agent.
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.
Cyclophospamide in combination with fludarabine. 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.
FC in combination with rituxumab
Following these initial considerations, the German CLL Study Group combined FC with rituximab. Rituximab is a monoclonal antibody against one of the surface proteins on the CLL cells called CD20. It therefore specifically targets the lymphoma cells and unlike chemotherapy is not harmful to the rest of the body. Its main side-effects are infusion-related. Especially after the first infusion, rituximab can cause an allergic reaction (skin rashes, shakes, fever, breathlessness etc). Rarely, this reaction can be severe and similar to a reaction after a bee sting. Additional medication to prevent these reactions is routinely given before each infusion.
The addition of rituximab to FC compared to FC alone has led to an improved overall survival for patients under the age of 70 and without other major health problems. This is the first time that a drug or drug combination has changed the natural cause of the disease. Another study showed that the use of FCR in relapse, mainly in patients who previously had received chlorambucil was also effective. On the basis of these two studies the National Institute of Clinical Excellence (NICE) approved FCR treatment in first line and in second line for patients fit enough to tolerate it. However, second line patients can only get rituximab on the NHS if they have not received it before, unless as part of a clinical trial. FCR combination treatment can cause serious side-effects. Its use is therefore limited to patients who are otherwise fit. 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.
Bendamustine is a chemotherapy agent that belongs to a class of drugs called alkylators. However, it shares some characteristics with purine analogues like fludarabine. Bendamustine has been available in Germany for several decades and has become a commonly used treatment for a variety of blood cancers there. The molecule was designed by German chemists who were trying to combine the properties of two types of chemotherapy agent (alkylators and anti-metabolites) in one drug. Consequently, bendamustine is sometimes called a ‘hybrid’ agent. Bendamustine is well tolerated and –unlike fludarabine- can be used in patients with kidney impairment as it is excreted through the liver. An important study comparing chlorambucil with bendamustine in patients who have never had any treatment for CLL showed that bendamustine worked in over 80% of patients and that the time to relapse was much longer then with chlorambucil. Bendamustine was well tolerated, although is caused slightly more infections then chlorambucil. On the basis of this and other evidence NICE approved bendamustine as an additional option for patients with CLL who cannot tolerate FCR treatment.
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 Bcell 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. In view of the poor outlook of Richter’s syndrome, ideally, patients should be entered into clinical trials.
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 works as well when given as an injection under the skin. 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 (see Prognostic Factors article on CLLSA website).
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 autoimmune 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 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 either high-dose methylprednisolone (HDMP), which is usually given intravenously for 5 consecutive days every month or pulsed dexamethazone. Like alemtuzumab, HDMP and pulsed dexamethazone are active in cases of CLL with p53 abnormalities.
HDMP or dexamethazone given in combination with alemtuzumab may be more effective than either agent on its own but this is still an experimental combination and needs to be used with extreme caution owing to its potential for serious side effects. The alemtuzumab and dexamethazone regimen is currently being evaluated in the UK CLL210 trial, which is specifically for patients with a p53 deletion or fludarabine refractory disease (see CLL trials in the UK article on CLLSA website).
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 hould 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.
2015 edit: several agents have now gained EMEA license and are beginning to come availble for treatment use by NHS see update
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 FCR or bendamustine, 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.
Maintenance treatment with alemtuzumab, rituximab, ofatumumab, lenalidomide or BCR inhibitors. 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 side-effects from the individual drugs and we are not certain of the long-term effects of taking these drugs over a long period of time. 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 treatment to settle the disease down before it causes any symptoms or complications. However, this approach is, as yet, entirely unproven.
Allogeneic stem-cell transplantation. Allografting is usually an option only for a small minority of patients such as patients who are young and fit and have got TP53 deletion. In allogafting 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 is that it is significantly 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.
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 such as in the case of TP53 deletions/mutations. 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 was Professor Terry Hamblin. 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.
updated March 2012