chronic lymphocytic leukemia (cll)
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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
71
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!
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