Chronic Lymphocytic Leukaemia

Question 1

… most common form of leukaemia in adults in Western countries.

Answer 1

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in Western countries.

Question 2

The incidence of CLL .. with age.

Answer 2

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.

Question 3

The aetiology of CLL is incompletely understood.

Answer 3

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.

Question 4

Genetic alterations

Many genetic alterations may be seen in CLL. As with all cancers, these promote abnormal cell growth, cell survival and genomic instability:

Answer 4

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

Question 5

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 …

Answer 5

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.

Question 6

The hallmark feature of CLL is .. due to the infiltration of malignant B lymphocytes.

Answer 6

The hallmark feature of CLL is lymphadenopathy due to the infiltration of malignant B lymphocytes.

Question 7

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.

Answer 7

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.

Question 8

Symptoms of CLL

Answer 8

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.

Question 9

Signs - CLL

Answer 9

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.

Question 10

Features associated with complications - CLLL

Answer 10

Autoimmune haemolytic anaemia: pallor, dyspnoea, weakness, dizziness
Immune thrombocytopaenia: petechiae, bruising, mucosal bleeding
Hypogammaglobulinaemia: recurrent infections (organ specific)

Question 11

The diagnosis of CLL is based on the presence of persistent …

Answer 11

The diagnosis of CLL is based on the presence of persistent lymphocytosis.

Question 12

The diagnosis of CLL is based on the presence of persistent lymphocytosis.

Answer 12

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.

Question 13

We have simplified the diagnostic criteria below:

Answer 13

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.

Question 14

Clinical and laboratory evaluation

The majority of patients with CLL are diagnosed incidentally on …

Answer 14

Clinical and laboratory evaluation

The majority of patients with CLL are diagnosed incidentally on a full blood count.

Question 15

The principle investigation in CLL is the…

Answer 15

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.

Question 16

Bloods - CLL

Answer 16

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

Question 17

SMEAR CELL

What leukaemia?

Answer 17

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

Question 18

Bone marrow assessment in CLL

Answer 18

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.

Question 19

IMAGING in CLL?

Answer 19

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.

Question 20

Other investigations for CLL

Answer 20

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

Question 21

CLL can be staged according to the … or Rai systems.

Answer 21

CLL can be staged according to the Binet or Rai systems.

Question 22

.. can be staged according to the Binet or Rai systems.

Answer 22

CLL can be staged according to the Binet or Rai systems.

Question 23

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.

Answer 23

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.

Question 24

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:

Answer 24

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

Question 25

In addition to the Binet and Rai system, other prognostic factors can be used to guide treatment.

Answer 25

Lymphocyte doubling time: number of months it takes for the lymphocyte count to double.
Genetic abnormalities: cytogenetic analysis of mutations including TP53, del(11q), trisomy 12, and del(13q)
Beta-2-microglobulin: correlates with disease stage and tumour burden
Others: e.g. Mutated immunoglobulin heavy chain variable genes, CD23 positivity and ZAP-70 positivity, among others.

Question 26

A variety of treatment options now exist for the management of CLL.

Answer 26

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.

Question 27

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:

Answer 27

Bone marrow failure (Hb < 100 g/L, plts <100 x10^9/L)
Massive, progressive or symptomatic splenomegaly (≥6 cm below costal margin)
Massive, progressive or symptomatic lymphadenopathy (≥10 cm)
Progressive lymphocytosis (≥50% over 2 months or doubling time < 6 months)
Autoimmune complications not responsive to steroids (e.g. ITP/AIHA)
Symptomatic/functional extranodal sites (e.g. skin, kidney, lung, spine)
Disease-related symptoms (e.g. significant weight loss, severe fatigue, >2 weeks of fever or ≥1 month of night sweats without infection)

Question 28

There are numerous therapies that can be used in the treatment of CLL. These depend on:

Answer 28

Patient fitness and performance status
Co-morbidities
Mutational analysis (e.g. TP53 mutations)
First-line treatment or treating relapse/refractory disease

Question 29

Cll common regimens are listed:

Answer 29

Front-line therapy (no TP53 mutations): Fludarabine, cyclophosphamide and rituximab (FCR)
Front-line therapy (TP53 mutations): Ibrutinib or Idelalisib and rituximab.
Treatment of relapsed/refractory disease: Ibrutinib or Idelalisib and rituximab.

Question 30

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:

Answer 30

Chemotherapy
Chlorambucil: cross-links DNA leading to damage and apoptosis. Given orally.
Fludarabine: purine analog that inhibits DNA synthesis. Given orally or intravenously.
Bendamustine: alkylating agent that cross-links DNA causing damage.
Small molecule inhibitors
Ibrutinib: tyrosine kinase inhibitor. Usually reserved for CLL with TP53 mutations
Idelalisib: phosphoinositide 3-kinase inhibitor. Often used in combination with rituximab in relapsed/refractory disease.
Venetoclax: BCL2 inhibitor. May be used in relapsed/refractory disease.
Monoclonal antibodies
Rituximab/Obinutuzumab/Ofatumumab: Anti-CD20 antibodies that target B lymphocytes (i.e. lymphocyte depleting agent)
Other
Corticosteroids: may be used as a single agent in extremely frail patients. May be prescribed to treat autoimmune complications including haemolytic anaemia and immune thrombocytopaenia.

Question 31

…: tyrosine kinase inhibitor. Usually reserved for CLL with TP53 mutations

Answer 31

Ibrutinib: tyrosine kinase inhibitor. Usually reserved for CLL with TP53 mutations

Question 32

Allogenic stem cell transplantation

Answer 32

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.

Question 33

Allogenic stem cell transplantation

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.

When is it considered in CLL?

Answer 33

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).

Question 34

CLL

Several aspects of care need to be addressed in all patients regardless of systemic therapy. These include:

Answer 34

Vaccination: influenza, pneumococcal (ensure no contraindication with current therapy)
Antibiotics for infections
Consider intravenous immunoglobulin: treatment of secondary hypogammaglobulinaemia (i.e. IgG < 5g/L)
Consider Pneumocystis jirovecii pneumonia (PJP) and herpes zoster prophylaxis: usually in patients on treatment for relapsed CLL

Question 35

In some patients, CLL may transform into another lymphoproliferative disorder.

Answer 35

Histological transformation

Richter transformation (3-7%): formation of an aggressive lymphoma. Associated with a rapid deterioration. Approximately 5-8 month median survival.
Prolymphocytic leukemia (2%)
Hodgkin lymphoma (0.5-2%)
Multiple myeloma (0.1%)

Question 36

Other complications

CLL

Answer 36

Secondary infections: herpes zoster, PJP, bacterial infections
Autoimmune complications: AIHA, immune thrombocytopaenia
Hyperviscosity syndrome: patients with a significantly elevated lymphocyte count are at risk (i.e. > 30 x10^9/L)
Secondary malignancies: increased risk of haematological (e.g. acute myeloid leukaemia) and solid-organ malignancies

Question 37

Prognosis in CLL has improved with the use of new therapeutic agents.

Answer 37

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:

Stage A: median survival >10 years
Stage B: median survival >8 years
Stage C: median survival 6.5 years

Question 38

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:

Stage A: median survival > years
Stage B: median survival >…years
Stage C: median survival …. years

Answer 38

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:

Stage A: median survival >10 years
Stage B: median survival >8 years
Stage C: median survival 6.5 years