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
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B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA TRISOMY FOR

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CHRONIC LYMPHOCYTIC LEUKEMIA 13q-CHROMOSOME ABNORMALITY

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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 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) • 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!

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