Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in Western countries.
Leukaemia refers to a group of malignancies that arise in the bone marrow. They are relatively rare but together are the 12th most common cancer in the UK, responsible for around 4,700 deaths a year.
There are four main types:
Presentation, prognosis and management all depend on the type and subtype of leukaemia.
CLL is considered a lymphoproliferate disorder of B lymphocytes, which results from an abnormal clonal expansion of B cells that resemble mature lymphocytes. This leads to widespread lymphadenopathy and secondary complications such as immune deficiency and cytopaenias.
CLL can present with a wide range of clinical manifestations relating to the condition or associated complications. Patients may be asymptomatic with indolent disease that remains stable for many years. Alternatively, patients may have progressive disease leading to death within 2-3 years of diagnosis.
The incidence of CLL increases with age.
The incidence of CLL is estimated around 4.2 per 100,000 per year and the condition is more common in men. The average age at diagnosis is around 72 years old. However, just over 10% of patients may be diagnosed before 55 years old.
The aetiology of CLL is incompletely understood.
The development of CLL occurs secondary to sequential genetic alterations and changes to the bone marrow microenvironment. Collectively, this promotes the formation of a clone of B lymphocytes that subsequently undergo further genetic changes that promotes proliferation leading to CLL.
Many genetic alterations may be seen in CLL. As with all cancers, these promote abnormal cell growth, cell survival and genomic instability:
An initial inciting event or abnormal reaction to an antigen stimulus leads to genetic alterations that allow the formation of a clone of B lymphocytes. This is a premalignant disorder, which is referred to as monoclonal B cell lymphocytosis (MBL). Overtime, further genetic mutations and bone marrow microenvironment changes promote the progression to CLL. This transformation from MBL to CLL occurs at a rate of 1% per year.
A proportion of patients who develop CLL may remain asymptomatic for many years. However, others may get rapidly progressive disease with complications associated with the defective immune function including cytopaenias and hypogammaglobulinaemia (i.e. low antibody levels). This can lead to recurrent infections, bleeding and features of anaemia. The symptomatic stage of CLL is characterised by progressive lymphadenopathy, which includes splenomegaly and hepatomegaly, that occurs due to the accumulation of incompetent lymphocytes.
The hallmark feature of CLL is lymphadenopathy due to the infiltration of malignant B lymphocytes.
A large proportion of patients may be asymptomatic. Therefore, the condition is detected on routine blood tests or the finding of abnormally enlarged, but painless, lymph nodes.
Typical ‘B’ symptoms may be seen in 5-10%, which is classically associated with lymphoma. This refers to fever, weight loss and drenching night sweats.
The diagnosis of CLL is based on the presence of persistent lymphocytosis.
The diagnosis of CLL is principally based on the presence of excess lymphocytes on full blood count that are found to be clonal (i.e. all of the same type). Clonality can be assessed by flow cytometry, which is a process that immunophenotypes cells. In other words, it can detect antigens expressed on the surface of cells, which are shared by the clonal lymphocytes.
Diagnosis is based on the 2018 international working group CLL (iwCLL) guidelines, which utilise the absolute B lymphocyte count, characteristic immunophenotype features, and presence or absence of disease manifestations. These manifestations include lymphadenopathy, hepatosplenomegaly, disease-related cytopaenias or disease-related symptoms.
We have simplified the diagnostic criteria below:
*NOTE: characteristic immunophenotype findings refer to expression of typical B-cell associated antigens (CD19, CD20, CD23), expression of CD5 T-cell antigen (also found on some mature B cells) and low levels of surface membrane immunoglobulins.
The majority of patients with CLL are diagnosed incidentally on a full blood count.
The principle investigation in CLL is the full blood count (FBC). This enables review of blood counts (i.e. haemoglobin, platelets, white cells) and the differentiation of white cells (e.g. lymphocytes, neutrophils).
As part of CLL work-up, patients require a thorough clinical examination and laboratory evaluation (i.e. blood tests). This enables confirmation of CLL, staging of the disease and assessment of disease-associated complications.
Essential to determine the presence or absence of lymph node involvement including specific sites, splenomegaly and hepatomegaly.
Immunophenotyping is used to confirm that lymphocytosis is secondary to circulating clonal B lymphocytes. Completed using flow cytometry of peripheral blood.
Cytogenetics involves looking for characteristic mutations. Specific mutations can be completed prior to treatment as it will influence decision making (e.g. TP53 mutation).
A blood film will confirm the presence of lymphocytosis and characteristically shows smear or ‘smudge’ cells. These are artefacts due to damaged lymphocytes that occur during preparation of the slide.
Assessment of bone marrow by aspirate or trephine biopsy is usually not required unless there is concern for an alternative diagnosis. If completed, will show replacement of normal marrow with excess lymphocytes.
May be indicated to show complete response to treatment or to determine the cause of cytopaenias.
Routine use of imaging (e.g. CT chest, abdomen, pelvis) is usually not required. However, CT may be indicated if concerns about lymphomatous transformation, to assess disease extent pre- and post-intensive treatment, or when a significant complication is suspected.
Ultrasound may be used to confirm hepatosplenomegaly. Chest x-ray may be useful to exclude an alternative diagnosis, assess for infection or look for pulmonary lymphadenopathy.
CLL can be staged according to the Binet or Rai systems.
Both the Binet and Rai systems are based on clinical features and laboratory evaluation (e.g. blood counts). They provide prognostic information in CLL.
This staging system is based on the number of lymphoid sites affected on clinical examination (cervical nodes, axillary nodes, inguinal nodes, spleen, and liver) in combination with presence or absence of anaemia/thrombocytopaenia.
NOTE: an area is counted as one regardless of whether unilateral or bilateral.
This staging system is based on the expected natural progression of CLL. As the burden of abnormal B lymphocytes increases, there is progressive lymphocytosis in the blood and bone marrow. This subsequently affects nodal tissue (e.g. lymphadenopathy, hepatosplenomegaly) and finally leads to bone marrow failure.
It was originally divided into five stages, which were subsequently grouped into three:
In addition to the Binet and Rai system, other prognostic factors can be used to guide treatment.
A variety of treatment options now exist for the management of CLL.
A watch and wait strategy may be appropriate in patients with asymptomatic, indolent disease without poor prognostic factors. This is usually for asymptomatic patients with Binet stage A/B or Rai stage <3.
Patients may have regular assessment and full blood count at 3 monthly intervals. At 12 months, treatment decisions can be decided based on the trajectory of the condition or develop of active/symptomatic disease.
Active disease needs to be clearly documented to initiate treatment. This means at least one criteria from the iwCLL needs to be met. We have simplified the criteria below:
There are numerous therapies that can be used in the treatment of CLL. These depend on:
The different pharmacological options are listed below. In general terms, treatment may be monotherapy or in combination. Some of the more common regimens are listed:
Different combinations of chemotherapy, small molecule inhibitors or monoclonal antibodies can be used in the treatment of CLL. We have detailed some of the choices that may be used:
An allogenic stem cell transplantation (AlloSCT) describes the process of transplantation of multipotent hematopoietic stem cells from a donor following chemotherapy to destroy the native bone marrow.
AlloSCT is a high-risk procedure that should only be considered in patients fit enough to undergo transplant. It is a potential option in patients who fail chemotherapy and BCR inhibitor therapy or those with TP53 mutations that do not respond to treatment or relapse. In addition, it can also be considered in those with Richter transformation (see complications).
Several aspects of care need to be addressed in all patients regardless of systemic therapy. These include:
In some patients, CLL may transform into another lymphoproliferative disorder.
Prognosis in CLL has improved with the use of new therapeutic agents.
The natural history of CLL is from an asymptomatic stage to a progressive, treatment-resistant phase that lasts 1-2 years.
The Binet and Rai staging systems also provide prognostic information. In Europe, the Binet system is widely used and provides median survival per stage. The following is according to the European Clinical Practice Guidelines for CLL:
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