Chronic Lymphocytic Leukemia (CLL) and Others Flashcards Preview

Heme/Onc > Chronic Lymphocytic Leukemia (CLL) and Others > Flashcards

Flashcards in Chronic Lymphocytic Leukemia (CLL) and Others Deck (32):
1

What are some distinctions and overlapping features of CLL and other lymphomas?

  • —Clonal leukemic proliferations of either B- or T-cell lymphocytes that have a “mature” phenotype
  • —Involve blood and bone marrow – may also infiltrate other organs such as lymph node and spleen
  • —Diseases of older adults
  • —Survivals months or years without therapy - usually considered incurable
  • —Leukemias initially manifest in bone marrow and blood while lymphomas present in lymph nodes, spleen, etc.
  • —Leukemias may involve lymph nodes
  • —Lymphomas may infiltrate blood and marrow
  • —Designation as leukemia or lymphoma may be arbitrary

2

What are the major classifications of CLL?

  • —B-Cell
    • —Chronic lymphocytic leukemia
    • —Hairy cell leukemia
    • —Prolymphocytic leukemia
  • —T-Cell
    • —Large granular lymphocyte leukemia
    • —Adult T-cell leukemia/lymphoma 
    • —Sézary syndrome
    • —Prolymphocytic leukemia
       

3

What is the epidiomology and etiology of CLL?

  • CLL most common leukemia in Western countries (rare in some Eastern countries such as Japan)
  • —Middle age to elderly
  • — M>F
  • —Etiology unknown
    • —Probable genetic predisposition
       

4

What are the features of small lymphocytic lymphoma (SLL)? How is it differentiated from CLL?

  • —No leukemia but lymph node or other tissue morphology and immunophenotype identical to CLL
  • —Much rarer than CLL
  • —CLL and SLL considered to be same diseases with different manifestations
  • —Designation CLL/SLL often used to include both diseases

5

What are some of the common peripheral blood findings at diagnosis for CLL?

  • —Elevated leukocyte count
    • —Clonal B lymphocytosis (>5000/uL) - small lymphocytes with condensed chromatin
    • —May be neutropenia
  • —Hb/Hct normal or decreased
  • —Platelet count normal or decreased
  • **Note: If there are <5000 clonal B cells, call it monoclonal B lymphocytosis.

6

What is monoclonal B cell lymphocytosis?

  • —6-7% of individuals >60 yr have monoclonal B-lymphocytosis (MBL) detected in PB (usually CLL-type immunophenotype)
  • —< 5000 clonal B cells in peripheral blood (arbitrary cutoff)
  • —No cytopenias, organomegaly, etc.
  • —Precursor lesion - ~1%/yr progress to CLL—

7

What are the clinical findings of CLL?

  • —Patients often asymptomatic
  • —Weakness, fatigue, weight loss
  • —Lymphadenopathy and/or splenomegaly may be present
  • —Infections – common complication, especially in later stages of disease
    • —Bacterial most common, especially with encapsulated organisms (i.e. Streptococcus or Staphylooccus) – often pneumonia
    • —Viral and fungal infections also occur  

8

What are some common histological findings of CLL?

  • White count elevated with anemia and thrombocytopenia
  • Large “smudge” cell on left common in CLL
  • All of the lymphocytes look alike – cookie cutter cells, same mold
  • Chromatin patterns are very condensed, no nucleoli, scant cytoplasm, textbook picture

9

What is the immunophenotype of CLL?

  • —Disease of activated, antigen experienced B cells
  • —Expresses B-cell antigens: CD19, CD20 (weak)
  • —Monotypic: low density surface Ig: IgM+/- IgD with kappa or lambda light chains
  • —Positive for CD5, a T-cell associated antigen
  • —Expresses CD23, an activation antigen

10

What is the importance of proliferation centers in CLL?

  • Can see a diffuse proliferation of lymphocytes, often will see a proliferation center
  • Some of the cells in the cells in these centers are bigger with nucleoli
  • Centers of mitosis, which keeps the disease going

11

What are the immune complications of CLL?

  • —Hypogammaglobulinemia - ~6-%
  • —Inability to make specific antibody
  • —Autoimmune disorders
    • —Autoimmune hemolytic anemia- ~10-25%
    • —Autoimmune thrombocytopenia- ~2%
  • —T cells also abnormal

12

What is the clinical course of CLL?

  • —Slowly progressive disease
  • —Survivals variable
    • —overall survival 10-15 years
    • —1/3 of patients: >25 years (never need therapy)
    • —1/3 of patients: more aggressive disease (med. survival – 8 yrs) – need therapy
       

13

Describe the clinical staging of CLL.

  • Stage 0 – lymphocytosis in blood and marrow
  • Stage 1 – lymphocytosis plus lymphadenopathy
  • Stage 2 – lymphocytosis with hepatomegaly   and/or splenomegaly
  • Stage 3 – lymphocytosis with anemia
  • Stage 4 – lymphocytosis with thrombocytopenia

14

Describe the genetics of CLL.

  • —High incidence (~ 80%) of clonal abnormalities but none specific for CLL
    • —Deletion 13q14 – most common (50%)
    • —trisomy 12 (20%)
    • —Deletions of 11q (site of ATM gene), 17p (TP53) less common
  • —Prognostic information
    • 13q sole abnormality – good prognosis
    • 11q,17p – poorer prognosis
  • About 50% of CLL’s exhibit somatic mutation of IgVH - good prognosis of survival
    • —Mutated CLL is associated with better survivals than unmutated CLL 

15

How often does CLL transform into a high grade  lymphoma?

  • —Diffuse large B-cell lymphoma
  • —Develops in 2-8% of CLL
  • —Majority (not all) clonally related to original CLL
  • —Survival  <1 year

16

What is the treatment for CLL?

  • —Traditionally “watch and wait” for early stage CLL
    • —Chlorambucil has been standard therapy
    • —CLL incurable
  • —Now more effective therapies
    • —Purine analogues, MoAb, transplantation
    • —Targeted therapy
       

17

What is Hariy Cell Leukemia?

  • —Rare clonal disorder of B lymphocytes
  • —Affects adults (median age ~55 years)
  • —Males >> females
  • —Etiology unknown

18

What are the clinical features of Hairy Cell Leukemia?

  • —Pancytopenia (50%) or cytopenias (100%)
    • —Leukocyte count usually low (neutropenia, monocytopenia)
    • —Hairy cells usually present but may be rare
    • —Anemia and/or thrombocytopenia frequent
  • —Peripheral lymphadenopathy usually absent
  • —Splenomegaly (80%)

19

What are the presenting signs and symptoms of hairy cell leukemia?

  • —Fatigue, weakness, weight loss
  • —Abdominal discomfort
  • —Infections
  • —Bleeding

20

What are the histologic and immunohistologic findings of hairy cell leukemia?

  • Histology
    • Hairy cells - membrane projections
    • Mone marrow core shows, cells wide apart (fried eggs)
  • Immunophenotype
    • —Express B-cell surface antigens (CD19,CD20)
    • —Monoclonal surface immunoglobulin
      • —Kappa or lambda
    • —Negative for CD5
    • —Positive for CD11c, CD25, CD103

21

What are the genetics of hairy cell leukemia?

  • —Gene sequencing identified BRAF mutation in majority/all HCL
  • —Mutation lies in activation loop of the kinase domain of BRAF – explains the activation of the Raf-MEK-ERK pathway in HCL
  • —BRAF mutation is key driver of HCL and a rational therapeutic target

22

What is the clinical course of hairy cell leukemia?

  • —Indolent, slowly progressive disease
  • —Complications include infection, bleeding
  • —Effective medical therapies
    • —>90% respond to purine analogue therapy
  • —Survival - years
     

23

What is large granular lymphocyte leukemia and what are the clinical characteristics?

  • —Rare disorder
    • —Most common in older adults (45-75 yrs)
  • —In most cases lymphocytes exhibit mature T cytotoxic phenotype (CD3+, CD8+, CD4-, CD56-/+, CD57+, CD16+, )
    • —Clonal T-cell receptor gene rearrangement
  • —STAT3 mutations in many LGLLs – involvement of JAK/STAT in pathogenesis 
  • Clinical Presentation
    • —Peripheral blood increase in LGL’s – no underlying cause
    • —Neutropenia (recurrent infections) most common, other lineages can be decreased
    • —Polyclonal hypergammaglobulinia
    • —Splenomegaly
    • —Subset have rheumatoid arthritis

24

What are the histologic findings and immunohistological characteristics of large granular lymphocyte leukemia?

Listen to lecture!

25

What is the clinical course of large granular lymphocyte leukemia?

  • —Clinical course variable
    • —Usually indolent
  • —No specific therapy
    • —Chemotherapy
    • —Steroids
       

26

What is adult T-cell Laukdemia/Lymphoma (ATLL)?

  • Aggressive malignancy of T-lymphocytes
  • First described in SW Japan; also occurs in Africa, Caribbean basin, northern areas of South America, and SW United States
  • Caused by HTLV-1 retrovirus - must be infected!
    • HTLV-1 integrated into DNA of T-lymphocytes
    • —Virus transmitted by:
      • blood transfusions
      • needle exchange
      • sexual contact
      • breast feeding
      • transplacentally
  • —Initial stage is carrier stage
  • —Disease expression occurs in adult (in small subset of carriers)

27

What are the histological and immunohistochemical findings of ATLL?

  • —Leukocyte counts variable; often >100,000/uL
  • —Lymphadenopathy, splenomegaly, skin lesions common
  • —May have hypercalcemia, bone lesions
  • —Abnormal lymphocytes have “flower-like” nuclei
  • —Lymphocytes are CD3+, CD7-, CD4+, CD8-, CD25+

28

What ist he clinical course of ATLL?

  • —Usually acute course with median survival 4-5 months
  • —Often unresponsive to chemotherapy
  • —More chronic forms also occur
     

29

What is Sezary Syndrome?

  • —Leukemic form of cutaneous T-cell lymphoma
  • —Generalized erythroderma
  • —Hyperkeratosis of palms and soles
  • —Pruritis
  • —Lymphadenopathy

30

What are the immunohistochemical and histological findings of Sezary Sydrome?

  • —Lymphoma cells with cerebriform nuclei
  • —Circulate in the blood (leukemic)
  • —Mature T- helper phenotype (CD3+, CD4+, CD8-)
  • —Cells express adhesion molecules that contribute to “homing” to skin—

31

What is the therapy of Sezary Syndrome?

  • —Primarily directed toward the erythroderma
  • —Topical or systemic
  • —Median survival – about 5 years—

32

What are the prominent features of T cell prolymphocytic leukemia?

  • —Rare leukemia of adults, 
  • —Hepatosplenomegaly and lymphadenopathy
  • —Lymphocyte count often >100x109/L
  • —Usually aggressive
  • —Most CD4+, subset CD4+/CD8+
  • —Most frequent genetic abnormality is inv(14) involving TCL1 → constitutive activation of TCL-1
    • —May respond well to Campath (monoclonal antibody to CD52)