Leukaemia Lecture 04

Leukaemia Lecture 04
Chronic Lymphocytic Leukaemia (CLL)

Leukaemia Lecture 04
Chronic Lymphocytic Leukaemia (CLL)
Dr. Rabiul Haque

Lecturer, Department of Pathology
Holy Family Red Crescent Medical College, Dhaka
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pathology video lectures.
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Learning Objectives
• Introduction
• Definition
• Classifications of Lymphoid Neoplasms
• Pathogenesis of CLL
• Clinical Features
• Laboratory Diagnosis
• Prognosis
• Staging of CLL
• Treatment
Introduction
• Chronic Lymphocytic Leukaemia (CLL) is the most
common form of leukaemia of adults in Europe and the
USA.
• It is the less frequent elsewhere.
• The median age of diagnosis is 60 years.
• It is twice as common in males as compared to females.
• It is an incurable disease and tends to run a chronic and
fluctuating coarse.
Definition of Chronic Lymphocytic Leukaemia
• Neoplastic disorder characterized by monoclonal
proliferation of immunologically incompetent, slowly
dividing, mature B-lymphocytes.
Monoclonal
Monoclonal Proliferation:
Proliferation:
Group
Group of
of cells
cells produced
produced from
from aa single
single
ancestral
ancestral cell
cell by
by repeated
repeated cellular
cellular
replication.
replication.
• If CLL is to be diagnosed there must be a monoclonal B-
cell count of > 5 × 109/L.
• If CLL is to be diagnosed there must be a monoclonal B-
cell count of > 5 × 109/L.
• Reference:
• Kawthalkar, S. M. (2013). Essentials of Haematology (2 nd Ed.).
New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.
• Hoffbrand, A. V., Moss, P. A. H. (2016). Hoffbrand’s Essential
Haematology (7th Ed.). West Sussex: John Wiley & Sons Ltd.
World Health Organization Classification of Lymphoid Neoplasms
• I. Precursor B-Cell Neoplasms

• II. Peripheral B-Cell Neoplasms
• III. Precursor T-Cell Neoplasms
• IV. Peripheral T-Cell and NK-Cell Neoplasms
• V. Hodgkin Lymphoma
B-cell acute lymphoblastic
• I. Precursor B-Cell Neoplasms leukemia/lymphoma (B-ALL)

B-cell acute lymphoblastic
• I. Precursor B-Cell Neoplasms leukemia/lymphoma (B-ALL)

Chronic lymphocytic leukemia / small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic and nodal marginal zone lymphomas
Extranodal marginal zone lymphoma
Mantle cell lymphoma
Follicular lymphoma
Marginal zone lymphoma
Hairy cell leukemia
Plasmacytoma/plasma cell myeloma
Diffuse large B-cell lymphoma
Burkitt lymphoma
• WHO classification scheme considers “Chronic

Lymphocytic Leukemia (CLL)” and “Small Lymphocytic
Lymphoma (SLL)” as one entity with different clinical
presentations.
• CLL presents primarily in peripheral blood and bone
marrow.
• SLL mainly involves lymph nodes and other
lymphoid organs.
Pathogenesis
Pathogenesis
●
CLL/SLL is a slowly growing tumor.
●
In CLL/SLL increase tumor cell survival seems to be more
important than tumor cell proliferation in the pathogenesis.
●
CLL/SLL cells contain high levels of BCL2 protein that inhibits
apoptosis.
– Chromosomal deletion leads to loss of genes encoding micro-
RNAs that are negative regulators of BCL2 protein.
– Signals generated by B cell receptor (BCR) or surface
immunoglobulin causes expression of genes that promote
survival of CLL/SLL cells.
●
Accumulation of the tumor cells causes suppression of normal B
cell function.
Clinical Features
Clinical Features
• The condition may remain asymptomatic.
• It may have an insidious onset.
• It may present with nonspecific clinical features.
Common Clinical Features
• Anaemia
• Enlargement of Lymph Node
• Splenomegaly and Hepatomegaly
• Haemorrhagic manifestations
• Susceptibility to infections
Anaemia
• Anaemia develops due to progressive replacement of
bone marrow by tumor cells.
• Anaemia may also develop due to hypersplenism and
autoimmune haemolysis.
Enlargement of Superficial Lymph Node
• It is a common finding in chronic lymphocytic leukaemia.

• The lymph nodes are usually non-tender, symmetrically
enlarged and discrete.
Haemorrhagic manifestations
• In cases of Chronic Lymphocytic Leukaemia with
thrombocytopenia, haemorrhagic manifestations are
seen.
Susceptibility to Infections
• There is increased susceptibility to infections due to
replacement of bone marrow by tumor cells.
• These tumor cells are immunologically incompetent and
causes hypogammaglobulinaemia.
Laboratory Diagnosis
Laboratory Diagnosis
• Diagnosis is based on peripheral blood picture, bone
marrow examination, immunophenotyping, cytogenetic
analysis and immunological study.
Peripheral Blood Picture
• Red cells show normocytic normochromic anaemia.
• Anaemia is usually mild to moderate.
• Total white blood cell count is increased.
• There is marked leucocytosis but less than that seen in CML
(50,000-200,000/μll).
• Typically more than 90% of leukocytes are mature small
lymphocytes.
• Smudge or basket cells (degenerated forms) are seen due to
damaged nuclei of fragile malignant lymphocytes.
• Platelet count is normal or moderately reduced.
Small Mature-looking Lymphocytes

Platelet
Platelet
Red Blood Cell

Platelet
Red Blood Cell
Smudge Cell
Bone Marrow Examination
• Four patterns of infiltration can be recognized on bone
marrow trephine biopsy. They are:
– Interstitial
– Nodular
– Diffuse
– Mixed
Individual
Individual neoplastic
neoplastic cells
cells are
are
– Interstitial found
found interspersed
interspersed between
between
– Nodular haematopoietic
haematopoietic cells
cells and
and fat
fat
Cells.
Cells.
– Diffuse
– Mixed
Individual
neoplastic cells
cells are
are
found interspersed
between
cells and
and fat
fat
Cells.
Cells.
– Diffuse
– Mixed
Well-defined
Well-defined round
round oror oval
oval
aggregates
aggregates ofof neoplastic
neoplastic
cells
cells are
are seen
seen that
that are
are non-
non-
paratrabecular.
paratrabecular.
Individual
neoplastic cells
cells are
are
found interspersed
between
cells and
and fat
fat
Cells.
Cells.
– Diffuse
– Mixed
Well-defined
Well-defined round
round oror oval
oval
Extensive
Extensive replacement
replacement ofof both
both aggregates
aggregates ofof neoplastic
neoplastic
haematopoietic
haematopoietic and
and fat
fat cells,
cells, cells
cells are
are seen
seen that
that are
are non-
non-
bone
bone marrow
marrow architecture
architecture isis paratrabecular.
paratrabecular.
effaced
effaced and
and appears
appears ‘packed’
‘packed’
Normal Bone Marrow
Interstitial Pattern of CLL

Fat Cell
Normal Bone Marrow

Fat Cell
Trabeculae
Normal Bone Marrow

Fat Cell
Trabeculae
Haematopoietic Elements
Normal Bone Marrow

Fat Cell
Trabeculae
Haematopoietic Elements
Normal Bone Marrow
Individual Neoplastic Cell

Nodular Pattern of CLL
Diffuse Pattern of CLL

Immunophenotyping
• Provides definitive diagnosis.
• Should be done in all cases before beginning therapy.
• CLL cells usually express membrane phenotype of early
B cells.
• The tumor cells express CD19, CD20 (weak), CD5,
CD23, and weak surface membrane immunoglobulin.
• A single light chain (either κ or λ) is expressed on the ) is expressed on the
surface of the tumor cells.
Cytogenetics
• There is no single cytogenetic abnormality specific for
Chronic lymphocytic leukaemia.
• The common abnormalities include 13q-, 11q-, trisomy 12,
17p-, and complex abnormalities.
• Some chromosomal abnormalities (e.g. 11q- or 17p-) are
associated with a poor outcome .
Immunological Studies
• In two-thirds of the patients hypogammaglobulinaemia is
seen.
• It may become severe as the disease progresses.
• In about 5% of the patients M band (monoclonal protein)
is observed.
Prognosis
Prognosis
• CLL is a diverse disease in terms of clinical behavior.
• Over the years, a variety of features have been used to
predict prognosis of CLL.
Staging of chronic lymphocytic leukaemia (CLL)
• There are 2 different systems for staging CLL.

– Rai system: used more often in the United States.
– Binet system: used more widely in Europe
Staging of CLL : Rai Classification
Stage
0 Absolute lymphocytosis >5 × 109/L
I As stage 0 + enlarged lymph nodes (adenopathy)
II As stage 0 + enlarged liver and/or spleen ± adenopathy
III As stage 0 + anaemia (Hb <100 g/L)+ ± adenopathy ± organomegaly
IV As stage 0 + thrombocytopenia (platelets <100 × 109/L)+ ± adenopathy ± organomegaly

Staging of CLL : Rai Classification
Doctors separate the Rai stages into low-, intermediate-, and high-
risk groups when determining the treatment options.
Stage 0 is low risk.

Stages I and II are intermediate risk.
Stages III and IV are high risk.
Staging of CLL : Binet Classification
Stage Organ enlargement Haemoglobin ( g/L ) Platelets ( x109/L )
A (50-60%) 0, 1 or 2 areas ≥100 ≥100
B (30%) 3, 4 or 5 areas ≥100 ≥100
C (<20%) Not considered <100 and/or <100

Stage Organ enlargement Haemoglobin ( g/L ) Platelets ( x109/L )
A (50-60%) 0, 1 or 2 areas ≥100 ≥100
B (30%) 3, 4 or 5 areas ≥100 ≥100
C (<20%) Not considered <100 and/or <100
CLL is classified by the number of affected lymphoid tissue groups (neck lymph
nodes, inguinal lymph nodes, axillary lymph nodes, spleen, and liver) and by
whether or not the patient has anemia or thrombocytopenia.
Stage A has low risk.
Stage B and C have high risk.

Other Prognostic Markers
• These staging systems cannot accurately predict those

patients in early stage who will have disease progression
and those who will remain indolent.
Other Prognostic Markers
• Recently, a growing number of biologic and molecular

markers are being used for more accurate assessment of
disease status and prognosis. They include:
– Somatic mutation status of the variable region of the
immunoglobulin heavy chain (IGVH).
– Presence of chromosomal abnormalities: del13q14.3,
del11q22-23, trisomy 12, del17p13 etc.
Somatic mutation status of the variable region of the
immunoglobulin heavy chain (IGVH)
• This can divide the disease into two groups.
• About 55% of CLL patients have mutated IGVH.
– They have indolent disease.
– Median survival time is about 24 years.
• CLL patients with unmutated IGVH have aggressive
disease.
– Median survival time is about 8 years.
Presence of chromosomal abnormalities
•
Abnormalities Prognosis
del13q14.3 good
del11q22-23 poor
trisomy 12 intermediate
del17p13 very poor

Treatment
Treatment
• It is an incurable disease and so approach is generally
conservative.
• With optimal management patient can usually lead a
relatively normal life for several years.
• Aim of treatment is symptom control rather than a normal
blood count.
• Many patients never need treatment.
• Treatment is given for troublesome enlarged lymph nodes
or spleen and when constitutional symptoms such as
weight loss or bone marrow suppression are present.
Treatment
• Various forms of therapy for suppression of disease
include:
– Chemotherapy
– Corticosteroids
– Radiotherapy
– Immunoglobulin Replacement
Chemotherapy
●
For many years the treatment has been based on the
combination of cytotoxic drugs (such as fludarabine, chlorambucil
and cyclophosphamide or bendamustine) together with a
monoclonal antibody against CD20, such as rituximab.
●
These agents are given together every 4 to 6 weeks.
●
In older or less fit patients a less intensive treatment plan is
provided which still involves chemotherapy and an anti CD20
antibody.
Corticosteroids
●
Helpful for treatment of autoimmune haemolytic anaemia and
immune thrombocytopenia.
●
Splenectomy is indicated in cases of CLL with autoimmune
haemolytic anaemia.
Radiotherapy
●
It is given for treatment of splenic/lymph node enlargement
causing compression problems.
Immunoglobulin Replacement
●
Useful for patients with hypogammaglobulinaemia and recurrent
infections, especially during winter months.
Thank You !
●
Subscribe to youtube.com/c/RabiulHaque for more
pathology video lectures.
●
Visit pathologytutorials.weebly.com for transcript of
uploaded lectures.
●
Visit facebook.com/Pathology.Tutorials for channel
updates.

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Leukaemia Lecture 04

Chronic Lymphocytic Leukaemia (CLL)

Dr. Rabiul Haque

• I. Precursor B-Cell Neoplasms

• II. Peripheral B-Cell Neoplasms

• II. Peripheral B-Cell Neoplasms

• WHO classification scheme considers “Chronic

• It is a common finding in chronic lymphocytic leukaemia.

Small Mature-looking Lymphocytes

Small Mature-looking Lymphocytes

Small Mature-looking Lymphocytes

Red Blood Cell

Small Mature-looking Lymphocytes

Red Blood Cell

Normal Bone Marrow

Interstitial Pattern of CLL

Normal Bone Marrow

Interstitial Pattern of CLL

Normal Bone Marrow

Interstitial Pattern of CLL

Interstitial Pattern of CLL

Individual Neoplastic Cell

Interstitial Pattern of CLL

Nodular Pattern of CLL

Diffuse Pattern of CLL

• There are 2 different systems for staging CLL.

0 Absolute lymphocytosis >5 × 109/L

I As stage 0 + enlarged lymph nodes (adenopathy)

II As stage 0 + enlarged liver and/or spleen ± adenopathy

III As stage 0 + anaemia (Hb <100 g/L)+ ± adenopathy ± organomegaly

IV As stage 0 + thrombocytopenia (platelets <100 × 109/L)+ ± adenopathy ± organomegaly

Stage 0 is low risk.

Stage Organ enlargement Haemoglobin ( g/L ) Platelets ( x109/L )

A (50-60%) 0, 1 or 2 areas ≥100 ≥100

B (30%) 3, 4 or 5 areas ≥100 ≥100

C (<20%) Not considered <100 and/or <100

Stage Organ enlargement Haemoglobin ( g/L ) Platelets ( x109/L )

A (50-60%) 0, 1 or 2 areas ≥100 ≥100

B (30%) 3, 4 or 5 areas ≥100 ≥100

C (<20%) Not considered <100 and/or <100

Stage A has low risk.

Stage B and C have high risk.

• These staging systems cannot accurately predict those

• Recently, a growing number of biologic and molecular

del17p13 very poor

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