“Welcome to the Family”
A Practical Guide for Newly Diagnosed CLL Patients and those close to them.
Written for CLLSA by Professor Chris Fegan MB, MD, FRCP, FRCPath
Consultant Haematologist School of Medicine Cardiff University September 2017
We all know that rarely do good things last forever, but our health is something we often take for granted until it is taken away. You’re reading this because either you, or someone close to you, has been diagnosed as having chronic lymphocytic leukaemia, usually known as CLL. It’s a devastating moment- leukaemia – cancer of the blood – a real smack between the eyes. Yes it’s cancer and with that diagnosis often comes memories of family or friends lost. You've heard stories of others and their treatments, or disturbing images from the television. CLL is the commonest leukaemia but many of you will never even have heard of it until now. The important word however in CLL is not “Leukaemia” but “Chronic”. Hence the stories and images on TV are almost never those of CLL patients as most of these patients are well and having a full and active life, although there are an unfortunate few, who for many reasons things do not have the outcome one would hope.
As in any family, you did not choose to become a blood member. Fate forced it upon you. But the CLL Family is made up of tens of thousands of CLL focused members. Laboratory researchers, nurses, doctors, therapists, dieticians and most importantly the over ½ million CLL patients around the world - and those close to them - all with the one goal, that of supporting patients to live fully with their illness, learn more about CLL and ultimately identify even better treatments, to enable patients to have a normal, full and active life.
If you take nothing else away from reading below just remember that CLL is an illness you can usually live well with – very often without requiring any specific treatment.
The aim of this Guide is to inform you where we are with regards to background research and knowledge, to provide you with tips of how to cope with the news that you – or someone close - has CLL and to stop it affecting your life more than absolutely necessary, if at all.
What is CLL?
As stated above CLL is a type of cancer but what is “cancer”
We now know that normal people produce all sorts of cancer cells every single day and these are destroyed by our immune system. For someone to develop cancer either the immune system is not working adequately - our immune system does get weaker with increasing age and some medications make it weaker - or the number of cancer cells being produced overwhelms our normal immune system. We all know that lung cancer is nearly always caused by smoking. Here smoking itself leads to so many lung cancer cells being produced that a normal immune system cannot destroy them all. We all know people who “smoke like chimneys” but don’t get lung cancer. This is because they have a very good immune system which is able to cope with all the extra cancer cells smoking produces, but we also know of people who have only passively smoked and developed lung cancer. In these people - largely for unknown reasons - their immune system was unable to cope with the relatively few lung cancer cells passive smoking produces.
“Leukaemia” literally translates as “white blood”. There are many differing types of white blood cells and CLL is a cancer of a particular type of white blood cell called a B lymphocyte. The term “Leukaemia” refers to bygone days when the treatment for many common conditions including heart failure, infections, allergies etc was to take blood from the patient to remove toxins/infections or anything else they thought was responsible. When the blood from leukaemia patients was taken it initially looked pink because of the high white blood count but when left on the bench the white and red blood cells would separate into white and red components- hence the term “Leukaemia”.
There is a common fallacy that cancer cells grow (divide) quicker than normal cells- that is simply incorrect in the overwhelming majority of cancers.
Ask yourself – Why do your hair and nails keep growing but arms and legs don’t once we reach adulthood? The answer lies in that hair and nails just produce cells regardless of need but other tissues only produce one cell for each cell that dies, hence they do not grow and remain the same size. The process of cell death is called apoptosis and in virtually all cancers- and CLL - there is a failure of apoptosis. Hence CLL cells do not die but continue living to accumulate leading to organ enlargement, replacement of normal cells in the bone marrow and general feelings of ill health – tiredness, weight loss, night sweats and fever- so called “constitutional” or “B” symptoms.
Ask yourself another question – Why is man the most successful living thing on planet earth?
We have evolved the most amazing biological systems through a process of gene mutation which ultimately led to better proteins, enzymes, sugars and ultimately cells, tissues and organs. So mutations helped us be all that being a human means. However, it also makes us vulnerable if the mutations that develop are potentially harmful, as in cancer – this is why we evolved an immune system to help counter-act potentially harmful mutations.
What causes CLL?
At present there are no proven causes for CLL. We know CLL is more common as we get older, is more prevalent in men and spares some ethnic groups – particularly those from the Far East. Recent studies have shown we inherit some of the risk of developing CLL from our parents and in fact 1 in 20 CLL patients have a relative with CLL or a very similar condition. So these inherited factors either increase the number of CLL cells we produce or inhibit our immune system’s ability to remove them, this is the subject of intense research by the CLL Family.
What we do know is that CLL probably arises from a B Lymphocyte being stimulated by some type of protein or sugar and at this moment in time it’s thought these could be from bacteria. The stimulation of B lymphocytes makes them grow, but eventually they acquire the ability to grow without needing the presence of stimulating bacterial or other proteins. This is proven to be the case in many types of non Hodgkin lymphoma to which CLL has many similarities. This is also the subject of intense research, as identification of the bacteria would bring the prospect of vaccination to prevent CLL, or the use of antibiotic therapy to eradicate bacteria and possibly treat CLL.
Other reported associations with CLL include low vitamin D levels and some association with sunshine. Although of interest, this is still very preliminary data and to date there are no studies showing that taking vitamin D prevents patients developing CLL or their CLL from progressing.
So at present the CLL Family know of nothing you have done or experienced that led to you or someone close to you developing CLL. Therefore, there is little to be gained by examining the past with “did this cause CLL…, what if……, did I catch it from….., did these tablets cause this, is it related to my previous x-rays”. Whatever the reason is for you or someone close having CLL is it is very unlikely you will ever find out. Instead of looking back as to “why me” or “why them” better to look forward and concentrating your efforts on keeping well despite having CLL.
How does CLL present?
CLL is a disease of thirds. We know that around 1/3 of CLL patients go to their doctor feeling unwell from their CLL- lymph node, liver or spleen enlargement, symptoms of anaemia, bruising or so called constitutional (B) symptoms – fever, drenching night sweats and/or weight loss of greater than 10%. For the other 2/3’s they were found by chance often from a routine blood test taken for another reason. Of these, half will still not have required treatment after 10 years whilst in the other half their disease will have woken up (progressed) leading to symptoms requiring the introduction of specific CLL therapies.
How advanced is my CLL?
As outlined above we now identify ~ 2/3rds of patients “by chance”. This is because we now perform many more routine, more sophisticated blood tests than we did in the past. The accuracy of blood analysers in the 1960’s, 70’s and early 80’s was not very good. Most patients diagnosed with CLL back then already had symptoms or signs from their disease, so typically presented to their doctor with a more advanced stage. However it was noted that those few CLL patients who were identified before they had symptoms or signs - usually from a blood test showing a high lymphocyte count - appeared to follow a similar pattern of disease. The high lymphocyte count was typically followed by lymph node, liver and spleen enlargement and finally the development of anaemia and low platelets - as the marrow filled up with CLL and interfered with the normal production of red blood cells and platelets.
So in the 1970’s two staging systems were proposed:
The Binet staging system uses the number of lymphoid tissue sites affected along with the haemoglobin and platelet count so that:
Stage A = 0-2 lymphoid sites affected
Stage B = 3-5 lymphoid sites affected
Stage C = Haemoglobin less than 10g/dl or platelets less than 100 x 109/l.
In the Binet system the 5 lymphoid sites are neck, armpit and groin nodes along with spleen and liver enlargement. If both sides of the neck are involved this is still only 1 site. Likewise if there is more than 1 node in a given area eg right side of groin, this is still only 1 site. This staging system was described before we had access to CT scanning so nodes identified on the CT scan outside the 5 areas described in the Binet system really should not be counted in a patient’s initial staging.
In the Rai system
Stage 0 = Lymphocyte count greater than 5 x 109/1
Stage i = As stage 0 plus enlarged lymph nodes
Stage ii = As stage 0 plus enlarged liver or spleen
Stage iii = As stage 0 plus Haemoglobin less than 11g/dl
Stage iv = As stage 0 plus platelet count less than 100 x 109/l
These staging systems were valuable because the survival of CLL patients correlated with how advanced their stage of disease was when they presented to their doctors.
So although as a group patients with Binet stage A survived much better than those with stage C, it was very evident that within stage A some patients had stable disease for decades whilst others progressed within a few months/years. The reasons why some patients with early stage CLL have stable disease whilst others progress, has been the subject of intense research by the CLL Family. Although it is still not fully understood we now have a much better understanding of why this happens for individual patients and have developed tests which are better able to predict- to varying degrees of accuracy – what will happen – so called prognostic markers. These tests range from quick and easy to perform blood tests, such as the time it takes for a patient’s lymphocyte count to double, β2 microglobulin and lactate dehydrogenase estimation, to the profile of the individual CLL cells themselves and what proteins they express, to highly complex genetic testing for chromosomal and DNA abnormalities and telomere length.
What can I do to stop my CLL progressing/affecting my health?
There is no evidence than anything you do as a patient will alter whether your CLL progresses or not. However, as outlined below stopping smoking, being vaccinated and being vigilant about infections and who and what you come into contact with is very important.
Why do doctors not recommend treatment for CLL straight away?
It seems odd. One would expect that treating a cancer such as CLL at the earliest stages would lead to a better outcome but often doctors recommend a “Watch and wait” approach or as many patients and their carers perceive it - “Watch and worry” or even “Do nothing”!!!
To date there is no evidence that treating patients found by chance or with asymptomatic stable disease leads to a better outcome in the long term. Another consideration is that to have CLL not requiring treatment is not that uncommon and insurers are usually very sympathetic to this- especially as ~2/3rds of patients are found by chance. However once treatment is initiated it is highly likely insurance premiums will rise. One also has to bear in mind that no treatment – no matter how expensive or effective - is guaranteed to have no side effects. So often the right approach for patients – indeed the overwhelming majority of patients at diagnosis - is to “Watch and Wait”.
Treatment for CLL should only be initiated when the CLL patient stands to benefit. Although a rising lymphocyte counts can be of concern to patients, unless it is accompanied by constitutional symptoms, lymph node, liver or spleen enlargement, falling haemoglobin or platelet count it is unlikely that you need immediate treatment, although a rising lymphocyte count may be a reason for re-assessment of your disease or closer monitoring of it.
What treatments are available?
The CLL Family has been working extraordinarily hard for over 50 years to find more effective treatments and hopefully cures. Up to the mid 1990’s we only had one proven effective treatment for CLL – the chemotherapy agent Chlorambucil which had been used since the late 1950’s. The CLL Family have together now developed over 12 licensed drugs and have progressed to multi-drug regimen including several containing no chemotherapy agents at all.
At present the standard treatments for patients requiring therapy are:
Fludarabine/Cyclophosphamide/Rituximab(FCR) or Bendamustine/Rituximab(BR) – these treatment regimens are typically used for fit patients, as they consist of moderately intensive chemotherapy. While unlikely to cause hair loss, nausea, vomiting or diarrhoea they do suppress the immune system making patients prone to serious and potentially life threatening infections. Rituximab is a monoclonal antibody which can lead to reactions when infused and again affects the immune system making patients prone to infections.
Chlorambucil/Monoclonal antibody combination therapy. Recent studies have shown that combining Chlorambucil with a monoclonal antibody – Rituximab, Obinutuzumab or Ofatumumab leads to a better response and outcome than Chlorambucil alone. These regimens are typically used in patient in whom it is felt that FCR or BR are not appropriate, largely because the risk of serious infection with Chlorambucil is less.
More recently a completely new kind of treatment has become available – small molecule signal inhibitors – ibrutinib and idelalisib. These agents are very effective indeed and as they are not chemotherapies they have an excellent side effect profile. Being so new the CLL family are undertaking intensive clinical studies to identify how best to use these very exciting – and costly!!! -agents. It has already been shown in previously untreated patients that ibrutinib is better than chlorambucil alone but to date we do not know if it is better than a chlorambucil/Monoclonal antibody treatment as initial treatment for those deemed not fit enough for FCR or BR or indeed if they are superior to FCR or BR for those fit enough for these regimens.
Recently there is the development of another completely new kind of non chemotherapy treatment which encourages the CLL cells to undergo apoptosis – i.e kill themselves a drug called Venetoclax. This is licensed for use in relapsed CLL but when best to use it – either before or after ibrutinib or idelalsib is yet to be fully determined.
At present the CLL Family across the world are conducting dozens of studies aimed at establishing how best to combine the various new agents with the traditional chemotherapy and monoclonal antibodies and in which order they should be used.
Future new approaches to treating/curing CLL involve boosting a patient’s own immune system to kill off the CLL cells. Although still not readily available some of these new treatments look very promising indeed but we need to learn more about just how effective they are and what side effects they may cause.
As well as specific treatments for advanced stage and symptomatic disease, CLL patients can develop two other problems even in early stage disease which may require specific treatment:
1) Infections- we know that patients with CLL have a higher risk of infection, even if they have the earliest stage of disease and do not require specific treatment for their CLL. They typically get infections easier than healthy individuals and it often takes longer for them to clear infections and recover. Indeed it has been shown that up to 50% of CLL patients die from infections. Therefore when patients ask “what can I do to help myself?” the first answer is STOP smoking as 50% of CLL patients who smoke succumb to a chest infection. It is important that patient receive vaccinations against the common pneumonia causing bacteria - Pneumococcus and Haemophilus Influenza B, and the meningitis preventing vaccine against Meningococcal C. The annual flu jab is also important but the majority of patients with CLL will not mount an immune response against that particular strain of flu. As important is to make sure that all those close to you have the flu vaccine as this is the most likely source of flu transmission to you. They will respond to a flu jab so they are protecting you by having it. However although shingles can be a not uncommon and very unwelcomed problem for patients with CLL they should not receive the shingles vaccine as it is a “live” vaccine and hence CLL patients can actually develop shingles form the vaccine!!
One of the reasons that CLL patients are prone to infections is they are unable to produce antibodies to fight infections. There is a simple blood test to show if you are one of the 10-20% of CLL patients with this particular problem. If you are prone to infections and your antibodies are low then antibodies can easily be infused every 3-4 weeks to reduce the infection risk.
Of course you are more prone to contract infections the more people you meet with infections, being in a particular infection risk environment eg a damp mouldy home, or consuming foods with active bacteria or fungus in them. Foods containing live bacteria or fungus – some cheeses, yoghurts and organic foods/drinks - which are non-pasteurised should be avoided altogether.
Should an infection develop you need to seek immediate medical help and receive antibiotics as soon as possible.
2) Auto-Immune Haemolytic anaemia – as mentioned above patients with CLL have a poorly functioning immune system. This can lead to your immune system damaging your own red blood cells. This can also happen in normal healthy people but is more common in patients with CLL and hence specific treatment may be required for this even if your CLL remains at an early stage.
If you are reading this it is because you are seeking information about CLL. Good communication is the cornerstone of living with CLL – both for patients and those close to them. Given that CLL behaves in such a diverse way it is very important to get accurate information from trusted sources. Your doctor and other medical staff in the clinic know that CLL can be very different in its behaviour and it can be very difficult to predict what will happen to you as an individual patient. However there is emerging data that patients looked after by a team who specialise in CLL actually do better. So it is worth enquiring if the physician looking after you has got a special interest in CLL or if they have links with the local/regional CLL specialist service.
There will usually be a CLL nurse in the clinic who should be able to provide you with useful written information which often contains links to web-sites for those who wish to know more. There are some excellent patient support and charitable web sites but some are not so good and in a few instances a bit scary!!!!!! This is largely due to the data being either out of date or just erroneous. A web site is only as good as the people who run it!!! Please remember, there is no such thing as a daft question so go back to your doctor or CLL nurse and ask for clarification.
The CLL Family knows that diagnosis is a difficult time for patients and their carer’s and is striving to remove the uncertainties and improve care and treatments. For patient and their carers it’s very important to understand as much as possible at the very beginning, exactly what CLL is, what it may or may not do to affect your life and what strides are being made to improve matters.
It is too early to say we have ”a cure” for CLL but much progress is being made and the overwhelming majority of patients with CLL will have a normal life expectancy – with some but by no means all!! - requiring treatment for their CLL. One day we hope you leave the CLL Family forever with your CLL cured and both you and those around you hopefully relatively untainted from the experience.