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Chronic Lymphocytic Leukemia• Definition• Etiology• Pathology• Clinical Findings• Laboratory Findings• Diagnostic Criteria• Differential Diagnosis• Investigations• Staging• Prognosis• Treatment

Vikkineshwaran

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Chronic Lymphocytic Leukemia (CLL)

• CLL is the most common leukemia in the western world.

• It is an adult leukemia that affects all organs.

• Disease of the elderly

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• Accumulation of nonproliferating mature-appearing lymphocytes in the blood, marrow, lymph nodes, and spleen–~99% cases: B cell

related–~1% cases: T cell

related

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• It is slowly progressive, with a predictable clinical course and survival of 25 years and often does not require therapy.

• Considerably less aggressive disorder than are the other leukemias.

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Etiology

• The cause of CLL is unknown• There is increased incidence in farmers,

rubber manufacturing workers, asbestos workers, and tire repair workers

• Genetic factors have been postulated to play a role in high incidence of CLL in some families

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Etiology

• Cytogenetics–clonal chromosomal abnormalities

are detected in approximately 50% of CLL patients – the most common clonal

abnormalities are:• trisomy 12• structural abnormalities of

chromosomes 13, 14 and 11–patients with abnormal karyotypes

have a worse prognosis

7B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA TRISOMY FOR CHROMOSOME 12 Karyotype

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CHRONIC LYMPHOCYTIC LEUKEMIA 13q-CHROMOSOME ABNORMALITY Karyotype

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CLL - Pathology

• Genetic change in B-cell clone• Proliferation exceeds

apoptosis• Gradual accumulation of

neoplastic B-lymphocytes – blood, marrow, nodes, spleen

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• Normal adult peripheral blood:–B-cell lymphocytes 30%

with surface immunoglobulins–T-cell lymphocytes 70%

without surface immunoglobulins

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• Very important to differentiate which type of lymphocytes are involved in the CLL (B cells or T cells)• Diagnosis of CLL can be done

morphologically, but distinguishing between T-cell and B-cell CLL requires testing for cluster differentiation (CD) antigens

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• Malignant B cells of CLL do not progress to the final stages of development, the plasma cells; – Appear to stop developmentally at earlier

B-lymphocyte stage of development

• CLL usually presents with elevated WBC count with many lymphocytes (lymphocytosis)

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Common Sx:

• Fever • Pallor• Fatigue• Shortness of breath• Easy bruising• Gingival bleeding• Weight loss• Frequent infections

Note: approximately 70% of patients are asymptomatic at the time of diagnosis

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CLL –clinical features

• Asymptomatic lymphocytosis• Marrow failure• Lymphadenopathy• Hepatosplenomegaly• ‘B-symptoms’• Immunodeficiency • Anemia/Thrombocytopenia

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“B symptoms”

• Systemic symptoms of – fever, – night sweats, and – weight loss

• associated with both Hodgkin's lymphoma and non-Hodgkin's lymphoma.

• The presence or absence of B symptoms has prognostic significance and is reflected in the staging of these lymphomas.

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Changes in other organs

• The lymph nodes, liver and spleen are characteristically involved.

• In nodes and spleen the normal architecture becomes completely effaced by the infiltrate of monomorphic small lymphocytes, and similar cells are present in the portal tracts of the liver.

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• Production of non-functional Ig, so there is a hypogammaglobulinemia.

• Other blood elements are also reduced, which is what usually brings patients in.

• There may be–anemia's, – thrombocytopenia's, or –neutropenia's.

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Small Cell Lymphocytic Lymphoma

• Sometimes, the predominant presentation is with lymph node involvement with little or no evidence of disease in the blood and marrow, when it is termed small cell lymphocytic lymphoma(SCLL).

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• The cells are round to oval and lack significant nuclear angularity or cleavage.

• The chromatin is coarse and clumped.

• benign mature small lymphocytes also have same characteristics

• It may be hard to tell them apart

Lymph node biopsy

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Laboratory and Radiographic Work-up:

• CBC with manual differential

• Peripheral smear• Flow cytometry• Chemistry studies

to check for organ dysfunction

• Lymph node biopsy

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lymphocytes

Normal

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These mature lymphocytes are increased markedly in number.

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• The CLL cells tend to fragment during preparation of the blood film, producing many “smudge cells'

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Diagnosis – Peripheral smear

Small, mature looking Lymphocytes

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Diagnosis – Flow Cytometry

Co-expression of CD5 and CD19,23

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Diagnostic criteria

1) A peripheral blood lymphocyte count of greater than 5 G/L, with less than 55% of the cells being atypical

2) The cell should have the presence of B cell-specific differentiation antigens (CD19, CD20, and CD24) and be CD5(+)

3) A bone marrow aspirates showing greater than 30% lymphocytes

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Differential diagnosis• Infectious causes– bacterial (tuberculosis)– viral (mononucleosis)

• Malignant causes– B-cell– T-cell• leukemic phase of non-Hodgkin lymphomas• Hairy-cell leukemia• Waldenstrom macroglobulinemia• large granular lymphocytic leukemia

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StagingRAI

Binet

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Staging – Rai

Stage Feature Median Survival

0 Lymphocytosis only >150 months

1 Lymphadenopathy 101

2 Spleno/Hepato megaly

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3 Anemia 19

4 Thrombocytopenia 19

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Staging - Binet

Stage

Features Survival

A Lymphocytosis and <3 areas of Lymphadenopathy

> 7 yrs

B Lymphocytosis and >3 areas of Lymphadenopathy

< 5 yrs

C Anemia (<10) or Thrombocytopenia (<100)

<2 yrs

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The clinical course and staging of chronic lymphocytic leukemia. Five stages are recognized in the 'Rai' classification.

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Prognostic Factors:

• Prognosis is based on RAI classification

• Treatment based on Binet classification

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Markers of poor prognosis

• Advanced Rai or Binet stage• Peripheral lymphocyte doubling time

<12 months• Diffuse marrow histology• Increased number of prolymphocytes

or cleaved cells• Poor response to chemotherapy• High 2- microglobulin level• Abnormal karyotyping

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CLL - median survival (years)

Early - lymphocytosis alone (>10y)

Late - marrow failure (3-4y)

35Dohner H et al. N Engl J Med 2000;343:1910-1916

Prognostic Variables: Cytogenetics

13q deletion

12q trisomy, Normal

11q deletion

17q deletion

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CLL - Complications

• Immune Deficiency: Recurrent infections, hypo-gammaglobulinemia, increased risk of secondary malignancies

• Immune dysregulation: Autoimmune Phenomena (ITP, AIHA)

• Richter’s Transformation: the leukemia changes into a fast-growing diffuse large B cell lymphoma

• Opportunistic infection (e.g. shingles, pneumonia)

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CLL - principles of treatment

‘Watch and Wait’

• Not usually curable with available therapy

• Treatments include – bone marrow transplants, – radiation, – chemotherapy, and – intravenous gamma globulin to help

prevent bacterial infections

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FYI: Umbilical cords look like smiley faces!