3.3 Chronic Lymphocytic Leukaemia

Question 1

Leukaemias are conditions characterised by a clonal increase in white blood cells in the peripheral blood or bone marrow

Typical illness presentation of CLL – usually affects elderly patients and is an incidental finding
- A 65 year old Chinese male presents with the problem of an incidental finding of ______________, he is otherwise asymptomatic
o Physical examination reveals _____________ and a small splenomegaly of 2 cm – CLL is usually diagnosed with the work-up of these enlarged lymph nodes
o Laboratory results – only abnormality is leukocytosis

Answer 1

leucocytosis and lymphocytosis;

small cervical lymph nodes

Question 2

Morphology of cells in CLL – peripheral blood film
- ______________ – most abundant cells, fragile and many are damaged in the smearing process leading
appearance of ____________
- Lymphocytes with prominent nucleolus may be seen in some types of CLL
- ____________ – up to half of lymphocytes in CLL

Answer 2

Mature lymphocytes;

smear cells;

Prolymphocytes

Question 3

Epidemiology of CLL
- Most common leukaemia in adults in the west, less common than _____________ in Singapore as a cause of lymphocytosis
o Ratio of male to female in TTSH is 1.2 (other reports 1.3 – 1.7)
o Median age at diagnosis in TTSH patients is 68 (range 32 – 93)

Natural history of CLL – an indolent B cell proliferation disorder

• Due to accumulation of malignant mature B lymphocytes over years
• Usually preceded by years of undiagnosed _________________
• Rate of accumulation varies – even upon diagnosis, many CLL patients show a slow accumulation of these malignant B cells that may accelerate in the later stages of disease
• As disease progresses, B cells accumulate in lymphoid tissues leading to lymphadenopathy and splenomegaly – can occasionally cause compressive symptoms
  o Bone marrow failure – due to malignant B cell accumulation leading to __________________
  o Transformation to high grade lymphoma (Richter’s) – may occur in later stages due to malignant B cells acquiring more mutations
• Other complications may or may not be related to the stage of disease, although they are found more commonly in later stage diseases
  o Autoimmune phenomenon – autoimmune haemolytic anaemia, autoimmune thrombocytopenia etc.
  o Predilection for infections – bacterial infections such as _____________

Answer 3

splenic marginal zone lymphoma;

monoclonal B cell lymphocytosis (MBL);

progressive anemia and thrombocytopenia, reduction in normal white blood cells e.g. neutropenia;

Pneumococcal and Haemophilus;

Question 4

Diagnosis
- A diagnosis of CLL can be made if the following criteria are satisfied
o Lymphocytosis > ____________
o Blood film shows small mature lymphocytes and smear cells
o Immunophenotype B cells, _______ positive, with a CLL score of 4-5
o Cytogenetics and molecular genetics
- Monoclonality of B cells are examined on flow cytometry

Normal: Mix of kappa and lambda light chain expressing B cells in ____________
CLL: Presence of a ______________ of lambda light chain-expressing B cells

Intensity of lambda B cell expression in malignant B cells is lower than normal B cells – Ig expression on cell surface will be weaker than normal

Immunophenotype of B cells in CLL – in this flow cytometry of all lymphocytes, CD19 and CD5 or CD23 are plotted
- Normal : CD19 is normally expressed on B cells (right of x-axis) and non-B cells (left of xaxis), _____ is usually expressed on T cells and a small population of B cells ______, a receptor for IgE, is expressed heterogeneously in B cells
- CLL: B cells all expresses CD5 and CD23
The more the clonal B cells expresses such features, the more confident the diagnosis of CLL

Answer 4

5 x 109/L;

CD5;

3:2 ratio;

monoclonal population;

CD5;

CD23

Question 5

Prognosis and staging of CLL – Rai and Binet staging
- Rai staging – lower stages show lymphocytosis without _____________ and higher stages show _____________
o Median duration of survival for a low Rai and high Rai stage are at least 10 years and 1.5 years respectively
- CD38 on cell surface can be easily analysed on a flow cytometer – higher expression shows a worse prognosis
- Accompanying cytogenic features can also change
prognosis and treatment
o CLL patients harbouring a _______________ have a median survival of only 3 years after combining all stages of disease
o A __________________ relates to a median survival of more than 10 years

o Cytogenic profile is found to be an a stronger prognostic marker than stage of disease and is independent of each other
- Immunoglobulin gene mutation status – more frequently used prognostic marker
o Patients with cells that have not undergone __________________ (reprogramming) has a worse prognosis than patients which cells have been somatically hypermutated

Answer 5

lymphadenopathies;

anaemia and/or thrombocytopenia;

deletion in the short arm of chromosome 17;

deletion in the long arm of chromosome 13;

somatic hypermutation at the germinal centre

Question 6

Treatment of CLL – not every patient requires treatment
- Routine practice not to treat CLL patients with a low risk
- A high staging (disease burden), symptomatic lymphadenopathy or splenomegaly is indicative of treatment
- Older strategy – chemotherapy and monoclonal antibodies (usually against ________________)
- Recently, targeted therapy is more in use – BKT is an important signalling molecule in CLL cell survival
o Inhibition of BKT is effective in controlling CLL, now a first line option for significant groups of CLL patients
o Other molecules known to play a role in CLL pathogenesis is__________________ – inhibitors of these pathways have been developed, currently in use for patients whose disease have relapsed after use of BKT inhibitors

Prophylaxis

• IV immunoglobulin is recommended for those with ________________ and recurrent bacterial infections – these patients are prone to infections
• Immunisation against _________________

Answer 6

CD20 on B cells;

PI3K and the BCL2 anti-apoptotic pathway;

hypo-gammaglobulinemia;

Pneumococcus, Haemophilus and seasonal influenza