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.

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

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

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B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA TRISOMY FOR

CHRONIC LYMPHOCYTIC LEUKEMIA 13q-CHROMOSOME ABNORMALITY

CLL - Pathology
Genetic change in B-cell clone Proliferation exceeds apoptosis Gradual accumulation of neoplastic B-lymphocytes blood, marrow, nodes, spleen

 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 Blymphocyte 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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Lymph node biopsy

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
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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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Normal
lymphocytes

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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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Staging
RAI Binet

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Staging Rai
Stage Feature 0 1 2 3 4 Lymphocytosis only Lymphadenopathy Median Survival >150 months 101

Spleno/Hepato megaly 71 Anemia Thrombocytopenia 19 19

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Staging - Binet
Stage Features A Survival

Lymphocytosis and <3 areas of > 7 yrs Lymphadenopathy

B C

Lymphocytosis and >3 areas of < 5 yrs Lymphadenopathy 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)

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Prognostic Variables: Cytogenetics

13q deletion 12q trisomy, Normal 11q deletion

17q deletion

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

CLL - Complications
Immune Deficiency: Recurrent infections, hypo-gammaglobulinemia, increased risk of secondary malignancies Immune dysregulation: Autoimmune Phenomena (ITP, AIHA) Richters 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!

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