Chronic Lymphocytic Leukaemia Flashcards
(38 cards)
… most common form of leukaemia in adults in Western countries.
Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in Western countries.
The incidence of CLL .. 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.
Genetic alterations
Many genetic alterations may be seen in CLL. As with all cancers, these promote abnormal cell growth, cell survival and genomic instability:
TP53 mutation: TP53 is the ‘guardian of the genome’ and major tumour suppressor gene. The mutation is linked to a poor response to treatment.
11q and 13q14 deletions
Trisomy 12: presence of an extra 12th chromosome
Overexpression of BCL2 proto-oncogene: suppresses programmed cell death (i.e. increases cell survival)
NOTCH1 mutation: normally regulates haematopoietic cell development
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 …
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 .. due to the infiltration of malignant B lymphocytes.
The hallmark feature of CLL is lymphadenopathy due to the infiltration of malignant B 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.
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.
Symptoms of CLL
Weight loss Fevers Anorexia Night sweats Lethargy 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.
Signs - CLL
Lymphadenopathy: seen in 50-90% of patients. Most commonly cervical, supraclavicular and axillary nodes.
Hepatomegaly: 15-25% at diagnosis. Usually mild hepatomegaly.
Splenomegaly: 25-55% of cases.
Features associated with complications - CLLL
Autoimmune haemolytic anaemia: pallor, dyspnoea, weakness, dizziness
Immune thrombocytopaenia: petechiae, bruising, mucosal bleeding
Hypogammaglobulinaemia: recurrent infections (organ specific)
The diagnosis of CLL is based on the presence of persistent …
The diagnosis of CLL is based on the presence of persistent lymphocytosis.
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:
CLL: Absolute B lymphocyte count >5.0 x10^9/L for >3 months with characteristic immunophenotype*
CLL: Absolute B lymphocyte count <5.0 x10^9/L but ≥1 cytopenias due to bone marrow infiltration with typical CLL cells
MBL: Absolute B lymphocyte count <5.0 x10^9/L and no disease manifestations of CLL
SLL: Absolute B lymphocyte count <5.0 x10^9/L with nodal, splenic or extra-medullary involvement, but no cytopenias
*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.
Clinical and laboratory evaluation
The majority of patients with CLL are diagnosed incidentally on …
Clinical and laboratory evaluation
The majority of patients with CLL are diagnosed incidentally on a full blood count.
The principle investigation in CLL is the…
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.
Bloods - CLL
FBC: lymphocytosis (may be extremely high) and normocytic anaemia
Routine biochemistry: U&E, bone profile, LFTs
Blood film: discussed below
Haemolysis screen (at risk of AIHA): Direct antiglobulin test (DAT), haptoglobin, LDH, unconjugated bilirubin, reticulocytes
Immunoglobulins: at risk of secondary hypogammglobulinaemia
SMEAR CELL
What leukaemia?
Blood film
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.
CLL
Bone marrow assessment in CLL
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.
IMAGING in CLL?
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.
Other investigations for CLL
Lymph node biopsy: can be performed if the diagnosis is unclear or there is concern about lymphomatous transformation.
Virology: important prior to initiation of treatment. Hepatitis B, hepatitis C, HIV +/- CMV
CLL can be staged according to the … or Rai systems.
CLL can be staged according to the Binet or Rai systems.
.. can be staged according to the Binet or Rai systems.
CLL can be staged according to the Binet or Rai systems.
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.
Stage A: <3 lymphoid sites
Stage B: ≥3 lymphoid sites
Stage C: presence of anaemia (<100 g/L) and/or thrombocytopaenia (<100 x10^9/L)
NOTE: an area is counted as one regardless of whether unilateral or bilateral.
Rai staging
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:
Stage 0 (lymphocytosis): 25% at initial diagnosis
Stage I-II (lymphocytosis + lymphadenopathy + organomegaly): 50% at initial diagnosis
Stage III-IV (lymphocytosis + anaemia or thrombocytopaenia +/- lymphadenopathy/ organomegaly): 25% at initial diagnosis
