Overview of chronic lymphocytic leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) & Small Lymphocytic Lymphoma (SLL) are both indolent (slow growing) types of B-cell non-Hodgkin lymphoma. Each year in Australia, about 1000 people are diagnosed with CLL, and about 300 people are diagnosed with SLL. CLL is the second most common indolent lymphoma. About 15 out of every 100 (15%) people diagnosed with lymphoma, will have CLL. SLL is less common, and around 5 out every 100 (5%) people diagnosed with lymphoma, will have SLL.
Although CLL has the word leukaemia in its name, it is essentially the same type of B-cell lymphocyte, blood cancer as SLL. The two are so similar, that in 2016, the World Health Organisation (WHO) regrouped CLL and SLL together. The only difference between the two, is where the cancer is located.
- Chronic Lymphocytic Leukaemia (CLL): most of the lymphoma cells are in the bloodstream (this is why it is called leukaemia)
- Small Lymphocytic Lymphoma (SLL): most of the lymphoma cells are in the lymph nodes
The cancerous (malignant) B-cells look normal under a microscope, but they are not fully developed (immature) and do not work properly.
Treatment and prognosis
Chronic lymphocytic leukaemia (CLL & SLL) is considered a chronic condition and in most cases, it is not curable. The aim of treatment is to keep the CLL/SLL under control for as long as possible. Treatment may include chemoimmunotherapy or targeted therapy. Some patients may never need treatment (around 10% of patients), however others may live between periods of treatment and remission.
Who does it affect?
Each year there are over 1200 Australians diagnosed with CLL (SLL). It affects nearly twice as many men than women. CLL is more common in people over 70 years of age and it is quite rare in people under 40 years of age.
Both CLL and SLL are indolent (slow growing) lymphomas, although CLL is much more common and tends to grow more slowly. Sometimes, these slow-growing lymphomas change into a more aggressive subtype which need to be treated in a different way. This is called ‘Ritcher transformation or syndrome’.
We do not know what causes CLL, but research is ongoing to try and find out more about it. There are certain things called risk factors which may increase the risk of developing this lymphoma subtype. The risk of developing CLL increases with age.
Symptoms of chronic lymphocytic leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) symptoms usually develop quite slowly over time. Many patients have no symptoms in the early stages and the diagnosis is made following a blood test or procedure done for another reason. For others, the disease is detected when symptoms occur and the patient goes to the doctor because he or she is worried, uncomfortable, or does not feel well.
People who do have symptoms may experience:
- Painless swollen lumps (lymph nodes), mainly in the neck, armpit or groin
- A tender lump or swelling in the upper left-hand side of the abdomen. This is caused by an enlarged spleen
- Feeling full even after eating only a small amount
- Fatigue (extreme tiredness or lack of energy)
- Shortness of breath
- Low blood counts such as:
- Anaemia (low haemoglobin)
- Thrombocytopenia (low platelets)
- Neutropenia (low neutrophils)
- These low blood counts can lead to fatigue, bruising easily and frequent infections or difficulty fighting off infections.
- Night sweats (these sweats generally are so intense they require linen and clothing changes due to their drenching nature)
- Unexplained weight loss
It is important to tell the doctor about all symptoms as it can influence the decision around the type of treatment and when to start.
Diagnosis chronic lymphocytic leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) is usually first picked up from the results of a blood test. A person with CLL will have a large number of lymphocytes in the blood and it is this result that may lead THE doctor to suspect CLL.
Sometimes other blood counts may be slightly abnormal as well, for example red blood cells and platelet counts may be low.
A biopsy is usually required to diagnose chronic lymphocytic leukaemia (CLL) andsmall lymphocytic lymphoma (SLL). A biopsy is a surgical procedure to remove part of or all of an affected lymph node or other tissue to look under the microscope by a pathologist to see what the cells look like. The biopsy can be done under local or a general anaesthetic depending on what part of the body is being biopsied. The biopsy can be done one of three ways:
- Fine needle aspirate
- Core needle biopsy
- Excisional node biopsy
An excisional node biopsy is the best investigative option, as it collects the most adequate amount of tissue to be able to do the necessary testing for a diagnosis.
If chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) is suspected, then further examination and testing of the lymphocytes are done using a method called flow cytometry. On the outside of CLL cells are markers called cell surface proteins, the pattern of these markers is called the immunophenotype, you could think of this like a fingerprint of the proteins on the cell surface. This test is used to distinguish CLL from other kinds of lymphoma or leukaemia.
Waiting for test resultscan be a difficult time. It may help to talk to family, friends or a specialist lymphoma care nurse.
Staging of chronic lymphocytic leukaemia (CLL)
Once a diagnosis of CLL/SLL is made, there are further tests that are required to see where else in the body the lymphoma has affected or is located. This is called staging. The staging of the lymphoma helps the doctor to know what the best treatment is for the patient.
The staging system used for CLL is quite different to that of other NHLs. Doctors utilise the Rai staging system or sometimes the Binet staging system (mainly used in Europe).
Rai staging system
In this staging system, CLL is divided into 5 different stages, from 0 (zero) to IV (4). This staging system classifies the lymphoma according to whether a patient has, or does not have, any of the following:
- Lymphocytosis, which means there are high levels of lymphocytes in the blood
- Lymphadenopathy, meaning a patient has enlarged lymph nodes
- Splenomegaly, which is an enlarged spleen
- Anemia, meaning low levels of red blood cells
- Thrombocytopenia, meaning low levels of platelets
- Hepatomegaly, which is an enlarged liver
Staging for small lymphocytic lymphoma (SLL)
As SLL mostly affects the lymph nodes, this is usually staged using the same staging system as other non-Hodgkin lymphomas. There are four stages from stage 1 (lymphoma in one area) through to stage 4 (lymphoma that is widespread).
- Early stage means stage 1 and some stage 2 lymphoma. This may also be referred to as ‘localised’. Stage 1 or 2 means that the lymphoma is found in one area or a few areas close together.
- Advanced stage means the lymphoma is stage 3 and stage 4, and it is widespread lymphoma. In most cases, the lymphoma has spread to parts of the body that are far from each other.
Staging scans and tests
The scans and tests needed for staging and before treatment can start may include:
- Positron emission tomography (PET) scan
- Computed tomography (CT) scan
- Bone marrow biopsy
- Lumbar puncture & magnetic resonance imaging (MRI) – If lymphoma is suspected in the brain or spinal cord
Patients may also undergo a number of baseline tests prior to any treatment commencing to check organ functions. These are often repeated during and after the treatment has completed to assess whether the treatment has affected the functioning of organs. Sometimes the treatment and follow-up care may need to be adjusted to help manage side effects. These may include:
- Physical examination
- Vital observations (blood pressure, temperature, & pulse rate)
- Heart scan
- Kidney scan
- Breathing tests
- Blood tests
It may take some time for all the necessary biopsies and tests to be done (an average of 1-3 weeks), but it is important for the doctors to have a complete picture of the lymphoma and the general health of the patient in order to make the best treatment decisions
Many of the staging and organ function tests are done again after treatment to check whether the lymphoma treatment has worked and the effect this has had on the body.
What is the ‘grade’ of small lymphocytic lymphoma (SLL)?
Lymphomas are also often grouped as either indolent or aggressive. Indolent lymphomas are usually slow growing and aggressive lymphomas are fast growing. The grade is also referred to as the clinical behaviour of the lymphoma. CLL and SLL is a low-grade lymphoma
Genetic testing in CLL & SLL
Genetic testing for CLL/SLL is recommended prior to the treatment starting. These are done to identify any abnormal chromosomal abnormalities prior to treatment is important to help the doctor ensure the best treatment is identified for the patient.
Until recently, all patients with CLL received the same standard first-line treatment. Due to scientific progress, it is found that some patients who have these abnormalities have better outcomes with targeted therapy (immunotherapy) rather than chemoimmunotherapy treatments.
Fluorescence in situ hybridisation (FISH) is a genetic test to look for common chromosomal abnormalities that predict the likelihood that various CLL treatments will be effective and durable. For this test, the cells collected are grown in the lab, then their chromosomes are looked at under a microscope. Because it takes time for the cells to divide, this test usually takes a few weeks to complete.
In some people with CLL, part of a chromosome may be missing. This is called a deletion. The most common deletions occur in parts of chromosomes 13, 11 or 17. Deletion of part of chromosome 11 or 17, or known as del(17p), is linked to a poorer prognosis. The loss of part of chromosome 13 – del(13q) is usually linked with a slower-growing disease and a better outcome.
IgHV mutation status is an important test to have, and this mutation status almost never changes over time, so usually not recommended to repeat over time. It is important because we know that patients with a ‘mutated’ IgHV immunoglobulin do much better with chemotherapy-based treatments than patients who are ‘unmutated’.
TP53 gene is another genetic test and is used as a predictive factor, to see whether there is a mutation. If a mutation is discovered this predicts a worse outcome and chemoimmunotherapy is not effective.
Patients who have been identified to have any of these damaged chromosomes, can help the medical team plan for the best treatment for the patient. These tests also give some information about how the CLL may behave in the long term, although it needs to be looked at along with other factors, such as the stage of CLL. A FISH test should be done prior to each treatment for all patients, as the chromosomal abnormalities can occur at a later date.
In summary:
- Test FISH and TP53 Mutation: before every treatment
- Test IgHV mutation status: before the first treatment
- Deletion 17p or del(17p): no chemotherapy
- TP53 mutation: no chemoimmunotherapy
- IgHV unmutated: no chemoimmunotherapy
- IgHV mutated: possible chemoimmunotherapy
Prognosis of chronic lymphocytic leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) is considered a chronic condition and in most cases, it is not curable. The aim of management for most patients is to keep the CLL under control for as long as possible. Some patients may never need treatment (around 10% of patients), however others may live between periods of treatment and remission (watch and wait or active monitoring). There are many good treatments for CLL available, and so it can be controlled for many years.
It is best to speak to your doctor about your individual situation, as everyone diagnosed with CLL has a different journey. Survival statistics you may read about can be difficult to interpret due to this reason.
CLL usually grows very slowly and you might have many years between courses of treatment. However, some people have a faster-growing form that is likely to need more frequent treatment. Certain mutations in the cells can make CLL more difficult to treat and are at a higher risk. See genetic testing in CLL/SLL section above.
In general, people with CLL at a lower stage (less disease) have a better prognosis than those with more advanced CLL. Most patients survive around 10 years however this varies depending on how the CLL behaves. There are new medications, such as targeted therapies, that are coming onto the market that are effective for patients with high-risk genetic mutations and alternatives to standard chemoimmunotherapy, which does not work well for this type of CLL with genetic mutations.
Treatment for chronic lymphocytic leukaemia (CLL)
Once all the results from the biopsy and the staging scans have been completed, the doctor will review these to decide the best possible treatment for a patient. At some cancer centres, the doctor will also meet with a team of specialists to discuss the best treatment and this is called a multidisciplinary team (MDT) meeting.
Doctors take into consideration many factors about the lymphoma and the patient’s general health to decide when and what treatment is required.
This is based on:
- The stage of lymphoma
- Symptoms (including the size and location of the lymphoma)
- How the lymphoma is affecting the body
- Age
- Past medical history & general health
- Current physical and mental wellbeing
- Patient preferences
If treatment is needed, the patient’s type and severity of the symptoms, age, overall health and degree of the thickness of the blood, will help determine which treatment is selected.
Early stage CLL (stage 1-3)
Many patients with early stage or limited disease may not need treatment straight away. Management for early stage disease includes:
Watch and wait or also known as ‘active monitoring’: The doctor will observe the patient closely for a period and only commence treatment when needed. Clinical trials have shown that there is no benefit to starting treatment prior to patients having a need to start treatment. This also delays patients receiving toxic therapy and living with the side effects. Some patients may never require treatment (around 10% of people).
Advanced stage (stage 3-4)
Until recent times, all patients with CLL or SLL were treated the same. Some patients have very slow growing disease and may not require treatment ever, some patients can live on active monitoring for many years before needing treatment. However, once the CLL becomes more advanced patients will need to start active treatment.
Scientists are starting to have more of an understanding of the biology of CLL and SLL and now know that some patients have genetic abnormalities than can determine why some patients may not need treatment and while others are more resistant, with a poorer prognosis.
Before receiving every treatment
Best practice has now realised that patients are now recommended to have a FISH test, IgHV test and genetic test for TP53, before the first and every following treatment.
If you are found to have any of these genetic abnormalities:
- Deletion 17p or del(17p): no chemotherapy
- TP53 mutation: no chemoimmunotherapy
- IgHV unmutated: no chemoimmunotherapy
- IgHV mutated: possible chemoimmunotherapy
Treatment for patients with CLL or SLL
For most patients chemoimmunotherapy is effective to achieve a remission (no signs of cancer). For those who have been identified to have a genetic abnormality a targeted therapy e.g. (ibrutinib or venetoclax) as a first line therapy, is found to be very effective.
The standard first line treatments for patients with no genetic abnormalities can include:
- Chemoimmunotherapy: chemotherapy and a monoclonal antibody
First line treatment for patients with genetic abnormalities such as 17p(del) or TP53 or IgHV unmutated CLL/SLL may, receive targeted therapies that include:
- Ibrutinib
- Venetoclax and Obinutuzumab
- Stem cell transplantation (only if suitable for certain patients, including those with advanced disease, or those with certain high-risk features)
- Clinical trial participation
Common side effects of treatment
There are many different side effects of the treatment and these are dependent on the treatment that has been given. The treating doctor and/or cancer nurse can explain the specific side effects prior to the treatment. Some of the more common side effects of treatment may include:
- Anaemia (low red blood cells carry oxygen around the body)
- Thrombocytopenia (low platelets that help bleeding and clotting)
- Neutropenia (low white blood cells help with immunity)
- Nausea and vomiting
- Bowel problems such as constipation or diarrhoea
- Fatigue (tiredness or lack of energy
The medical team, doctor, cancer nurse or pharmacist, should provide information about:
- What treatment will be given
- What are the common and possible side effects for the treatment
- What side effects do you need to report to the medical team
- What are the contact numbers, and where to attend in case of emergency 7 days a week and 24 hours per day
Fertility
Some treatments for lymphoma can reduce fertility andhis is more likely with certain chemotherapy regimens (combinations of drugs) and high-dose chemotherapy used before a stem cell transplant. Radiotherapy to the pelvis also increases the likelihood of reduced fertility. Some antibody therapies may also affect fertility, but this is less clear.
The doctor should advise on whether fertility may be affected and if fertility preservation should be considered before treatment starts (if this is an option).
Follow-up care
Once treatment has completed, post treatment staging scans are done to review how well the treatment has worked. The scans will show the doctor if there has been a:
- Complete response (CR or no signs of lymphoma remain) or a
- Partial response (PR or there is still lymphoma present, but it has reduced in size)
If all goes well regular follow-up appointments will be made for every 3-6 months to monitor the below:
- Review the effectiveness of the treatment
- Monitor any ongoing side effects from the treatment
- Monitor for any late effects from treatment over time
- Monitor signs of the lymphoma relapsing
These appointments are also important so that the patient can raise any concerns that they may need to discuss with the medical team. A physical examination and blood tests are also standard tests for these appointments. Apart from immediately after treatment to review how the treatment has worked, scans are not usually done unless there is a reason for them. For some patient’s appointments may become less frequent over time.
Relapsed or refractory CLL
After treatment, the majority of patients can have a period of remission (no signs of CLL or when the CLL is under control) that lasts for years. However, CLL usually relapses (comes back) and a different treatment is given again with the aim of achieving remission again.
Most patients need several types of treatment for their CLL/SLL. Experts are discovering new and more effective treatments that are increasing the length of remissions. If the CLL does not respond well to the treatment or there is a relapse very quickly after treatment (within six months) this is known as refractory CLL and a different type of treatment will be needed.
At the time of relapse, the choice of treatment will depend on several factors including.
- How long the remission was
- General health and age
- What CLL treatment/s have been given
- Patient preference
This pattern may repeat itself over many years. New targeted therapies are available for relapsed or refractory disease and some common treatments for relapsed CLL can include the following:
Transformed CLL
In rare cases CLL can suddenly transform (change) into a more aggressive (fast growing) type of lymphoma, usually diffuse large B-cell Lymphoma (DLBCL) This is known as Richter’s transformation or Richter’s syndrome (RS). In very rare cases CLL can transform into Hodgkin lymphoma. Some symptoms that doctors may look for that may indicate that the CLL has transformed are:
- Sudden swelling of your lymph nodes (Lymphadenopathy)
- Developing B Symptoms (night sweats, weight loss, fevers)
- Change in certain chemical levels in your blood tests (Lactate dehydrogenase, LDH)
- Low haemoglobin (Anaemia)
- Low Platelets (Thrombocytopenia)
If the treating team suspects RS they will need to do a biopsy to confirm this. They may also need to do a PET or CT scan to get a better idea of how widespread the disease is.
RS is a serious complication of CLL that can be difficult to treat and does not always respond to treatment. The type of treatment for RS will depend on the subtype of lymphoma eg DLBCL or HL. Many people with transformed CLL are older, have received prior therapy and may have other medical conditions. This means that intensive treatment may not be suitable.
The most likely treatment is chemotherapy followed by a stem cell transplant. If this is not suitable for you then your doctors may suggest a less intensive approach aimed at keeping your symptoms under control for as long as possible known as palliative care.
Treatment under investigation
There are many treatments and new treatment combinations that are currently being tested in clinical trials around the world for patients with both newly diagnosed and relapsed CLL. Some therapies under investigation are;
- Venetoclax combination therapy
- Chimeric antigen receptor T-cell therapy (CAR T-cell therapy)
- Acalabrutinib
- Zanubrutinib
What happens after treatment
Late Effects
Sometimes a side effect from treatment may continue or develop months or years after treatment has completed. This is called a late effect.
Finishing treatment
This can be a challenging time for many people and some of the common concerns can be related to:
- Physical
- Mental wellbeing
- Emotional health
- Relationships
- Work, study, and social activities
Health and wellbeing
A healthy lifestyle, or some positive lifestyle changes after treatment can be a great help after the treatment has been finished. Making small changes such as eating and increasing fitness can improve health and wellbeing and help the body to recover. There are many self-care strategies that can help during the recovery phase.
