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The Chronic Lymphocytic Leukemias

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Hairy cell leukemia also has a characteristic phenotype, which is different from that of CLL and other lymphoproliferative disorders that can involve the blood ... – PowerPoint PPT presentation

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Title: The Chronic Lymphocytic Leukemias


1
The Chronic Lymphocytic Leukemias
Blood-Hematopoiesis-Lymphatics 2013
  • Brad Gehrs, MD
  • Department of Pathology bradley-gehrs_at_ouhsc.edu

2
Downloading this presentation or using any of the
diagrams, charts or photographs for any purpose
other than studying for the Blood-Hematopoiesis-Ly
mphatics course is prohibited.
3
Chronic Lymphoproliferative Disorders
  • Variety of conditions featuring neoplastic
    proliferations of mature lymphocytes in blood

4
Chronic Lymphoproliferative Disorders
Mature B-cell disorders B-cell chronic
lymphocytic leukemia (CLL) B-cell prolymphocytic
leukemia Splenic marginal zone lymphoma Hairy
cell leukemia Lymphoplasmacytic
lymphoma Leukemic phase of non-Hodgkin
lymphoma Plasma cell leukemia
5
Chronic Lymphoproliferative Disorders
Mature T-cell / NK cell disorders T-cell
prolymphocytic leukemia T-cell large granular
lymphocytic leukemia Aggressive NK cell
leukemia Adult T-cell leukemia/ lymphoma Sezary
syndrome
6
B-Cell Chronic Lymphocytic Leukemia (CLL)
  • Most common adult leukemia in U.S. Western
    Europe
  • 30 of all leukemias
  • Predominantly older age group
  • Median age 55-60 years at diagnosis
  • Does occur at younger ages
  • Men gt Women

7
CLL Biologic Heterogeneity
  • CLL is biologically heterogeneous
  • Pre-germinal center variant
  • Unmutated immunoglobulin gene (IgH)
  • More aggressive
  • Post-germinal center variant
  • Mutated immunoglobulin gene (IgH)
  • Less aggressive
  • Appearance and phenotype generally the same

8
B-Cell CLL Etiology
  • No known cause in the majority of patients
  • Possible genetic predisposition
  • Increased incidence in relatives of CLL patients
  • Possible occupational or chemical exposure
  • Reported increased incidence in agricultural
    workers

9
B-Cell CLL Clinical
  • Frequently asymptomatic Unexpected finding on
    routine CBC
  • Symptoms (when present) nonspecific
  • Fatigue, weight loss, fever, night sweats
  • Physical exam Often unremarkable
  • Lymphadenopathy may be present, but usually not
    marked
  • May have hepatosplenomegaly

10
B-Cell CLL Diagnosis
  • Lymphocytosis (gt5,000/mL)
  • Immunophenotyping by flow cytometry
  • Immunoglobulin light chain restriction (k or l
    light chain, but not both)
  • Characteristic phenotype
  • Bone marrow examination
  • Traditionally done, but may not be required

11
B-Cell CLL Blood Smear
  • Lymphocytosis of small, mature-appearing
    lymphocytes
  • Very condensed nuclear chromatin (Soccer ball
    nuclei)
  • Numerous smudge cells (smashed lymphocytes)

12
B-CLL Blood Smear
Low power
13
B-CLL Blood Smear
Smudge Cell
14
B-CLL Bone Marrow Biopsy
15
B-Cell CLL Phenotype
  • Expression of B-cell markers (CD19, CD20)
  • Expression of CD5 (T-cell marker)
  • Dim surface immunoglobulin, with light chain
    restriction
  • Other markers CD23, FMC-7-, CD38 variable
  • CD38 expression may be adverse indicator

This could appear on the USMLE.
16
B-CLL Laboratory Findings
  • Anemia and/or thrombocytopenia
  • 30 at diagnosis, usually mild
  • Absolute neutrophil count usually normal percent
    neutrophils decreased
  • Direct antiglobulin (Coombs ) test
  • 1 positive at diagnosis increases with
    duration of disease
  • Other labs usually unremarkable

17
B-Cell CLL Differential Diagnosis
  • Reactive lymphocytosis
  • Viral other infections
  • Drugs
  • Monoclonal B-cell lymphocytosis (MBL)
  • Prolymphocytic leukemia, T/NK-cell leukemias,
    hairy cell leukemias
  • Other non-Hodgkin lymphomas with blood
    involvement
  • Mantle cell, follicular lymphomas, others

18
Monoclonal B-Cell Lymphocytosis (MBL)
  • Presence of a small monoclonal B-cell population
    in blood
  • By definition, less than 5,000 clonal
    lymphocytes/mL (lt 5 x 109/L)
  • Other criteria
  • Normal physical exam (no lymphadenopathy or
    hepatosplenomegaly)
  • No B symptoms
  • No autoimmune or infectious disease

19
Monoclonal B-Cell Lymphocytosis (MBL)
  • Relatively common increases with age
  • Estimated gt4 of people over 40
  • Majority have same phenotype as CLL
  • MBL probably precedes all cases of CLL
  • However Majority of MBL never transform to CLL
  • No treatment for MBL

20
B-CLL Distinction from Small Lymphocytic
Lymphoma (SLL)
  • Distinction based on presence or absence of blood
    involvement
  • CLL gt5,000/mL clonal lymphocytes
  • SLL lt5,000/mL clonal lymphocytes
  • Phenotype, appearance in lymph node bone marrow
    identical
  • Considered one disease in WHO classification
    B-CLL/SLL

21
B-CLL Staging
  • Two systems Rai and Binet
  • Rai (or modified Rai) used in U.S.
  • Binet used in Europe
  • Both use lymphadenopathy bone marrow compromise
    as significant variables
  • Both helpful in predicting prognosis
  • However, some patients with low stage at
    diagnosis follow aggressive course

22
Rai Staging System for CLL
0 lowest IV highest
Dont memorize this table - Learn the general
concept
23
Binet Staging System for CLL
A Low B Intermediate C High
Dont memorize this table - Learn the general
concept
24
B-CLL Clinical Course
  • Majority have indolent course
  • Median survival gt10 years
  • Some patients live gt20 years without treatment,
    with few problems
  • Minority of patients have aggressive course
  • Survival only a few years

Older patient with stage 0 CLL may have normal
life expectancy for age
25
B-CLL Predictors of Aggressive Course
  • Rapid lymphocyte doubling time
  • Doubling time lt 12 months
  • Presence of cytogenetic abnormalities
  • Diffuse involvement of bone marrow
  • Bone marrow compromise
  • Advanced Rai or Binet stage

Rate of increase in lymphocyte count is more
important than the lymphocyte count itself
26
CLL Predictors of Aggressive Course
  • Unmutated immunoglobulin heavy chain gene (versus
    mutated IgH gene)
  • Expression of CD38
  • Expression of ZAP-70
  • Specific chromosomal abnormalities
  • p53 gene mutations
  • Trisomy 12
  • ATM gene mutations

27
B-CLL Complications
  • Infections
  • Cytopenias
  • Autoimmune disorders
  • Mass effects
  • Due to bulky lymphadenopathy
  • Transformation to histologically aggressive
    disease

You need to know these.
28
B-CLL Infections
  • Most frequent cause of death
  • Predominantly due to hypogammaglobulinemia
  • Poor opsonization
  • Impaired response to new antigenic challenges
  • Respiratory tract most common site
  • Other mucosal surfaces also

29
B-CLL Infections
  • Bacterial infections most common
  • Organisms
  • Strep. pneumoniae
  • H. influenzae
  • Staph. aureus
  • Gram-negative enterics
  • Pseudomonas species

30
B-CLL Infections
  • Patients treated with fludarabine prone to
    opportunistic infections
  • Pneumocystis carinii
  • Listeria
  • Mycobacteria
  • Nocardia
  • Aspergillus
  • Herpes viruses

31
B-CLL Cytopenias
  • Multi-factorial
  • Replacement of bone marrow
  • Autoimmune phenomena
  • Immune hemolytic anemia pure red cell aplasia
  • Immune thrombocytopenia (rare)
  • Hypersplenism
  • Treatment

32
B-CLL Autoimmune Phenomena
  • Predominantly directed against blood cells
  • Positive direct antiglobulin (Coombs ) test
    common
  • Hemolytic anemia less common
  • Resembles idiopathic warm autoimmune hemolytic
    anemia
  • Immune thrombocytopenia occurs, but uncommon

33
B-CLL Histologic Transformation
  • Development of large cell lymphoma (Richter
    syndrome)
  • Occurs in 3-5 of patients
  • Poor response to therapy short survival
  • Prolymphocytic transformation
  • Majority of lymphocytes in blood larger, with
    prominent nucleoli
  • Histologic transformation uncommon

You need to know about Richter syndrome
34
B-CLL Treatment
  • Some patients never require treatment for CLL
  • Indications for treatment
  • Rapid lymphocyte doubling time
  • Bulky lymphadenopathy
  • Bone marrow compromise
  • Autoimmune phenomena
  • Lymphocytosis per se is not an indication for
    treatment

35
B-CLL Treatment
  • Traditional Chlorambucil prednisone
  • Controls WBC count
  • Few or no complete responses
  • Fludarabine Becoming treatment of choice for
    many hematologists
  • Can induce complete responses
  • However Myelosuppressive immunocompromising
  • Monoclonal antibody therapy (Rituxan)

36
B-CLL Allogeneic Stem Cell Transplant
  • Considered for young patients with aggressive
    disease, histocompatible donor
  • Potential for cure of disease
  • Graft versus leukemia effect
  • Significant morbidity mortality
  • Most patients too old for allogeneic transplant

37
Hairy Cell Leukemia (HCL)
  • Uncommon, distinctive lymphocytic leukemia
  • Occurs predominantly in older population
  • Men gt women (3-5 1)

38
Hairy Cell Leukemia Characteristics
  • Cytopenias
  • Leukopenia, anemia, thrombocytopenia
  • Neutropenia monocytopenia common
  • Splenomegaly Often massive
  • Distinctive hairy lymphocytes in blood
  • May be uncommon

39
Hairy Cell Leukemia
40
Hairy Cell Leukemia Bone Marrow
Fried Egg appearance
41
Hairy Cell Leukemia Clinical
  • Nonspecific symptoms
  • Fatigue, weakness, lethargy
  • Abdominal discomfort, early satiety
  • Due to splenomegaly
  • Recurrent pyogenic infections
  • Due to neutropenia
  • Cutaneous infections common

42
Diagnosis of Hairy Cell Leukemia
  • Flow cytometry Key diagnostic test
  • Demonstrate clonality of lymphocytes
  • Characteristic phenotype
  • TRAP stain
  • Tartrate-resistant acid phosphatase
  • Older test used to diagnose HCL
  • Neither specific nor 100 sensitive
  • Might appear on USMLE

43
HCL TRAP Stain
  • Characteristic cytochemical reaction in HCL
  • Normal lymphocytes Acid phosphatase enzyme,
    inhibited by tartaric acid
  • HCL cells Enzyme resistant to tartaric acid
  • Tartrate Resistant Acid Phosphatase (TRAP)

Replaced by flow cytometry as the diagnostic test
of choice but might appear on examinations
44
TRAP Stain
Acid phosphatase reaction after incubation with
tartaric acid
45
HCL Treatment Survival
  • Survival previously 3-5 years
  • Now Dramatically effective therapies
  • Cladribine (2-chlorodeoxyadenosine)
  • Single 7-day infusion causes durable complete
    responses in gt80
  • Others
  • Pentostatin (2-deoxycoformycin) Also effective
  • Interferon-a Replaced by Cladribine

46
Adult T-Cell Leukemia/Lymphoma (ATLL)
  • Lymphocytosis of neoplastic T-cells with
    multilobated or convoluted nuclei
  • Common in southern Japan, parts of Caribbean,
    West Africa
  • In U.S. Most common in Southeast
  • African-Americans gt Caucasians

47
Adult T-Cell Leukemia/Lymphoma
48
ATLL HTLV-1
  • Geographic localization of ATLL corresponds to
    areas of endemic human T-cell lymphocytotrophic
    virus-1 (HTLV-1)
  • First virus proven directly oncogenic in humans
  • Demonstration of positive serologies for HTLV-1
    required for diagnosis of ATLL

49
ATLL HTLV-1
  • RNA retrovirus
  • Similarities to, but different family from HIV
  • Infects same cells (CD4 lymphocytes)
  • Encodes many proteins with similar structures
    functions

50
Adult T-Cell Leukemia/Lymphoma
  • May present as leukemia, lymphadenopathy
  • May present as lymphoma
  • Lymphadenopathy without blood involvement
  • Most patients eventually develop leukemic
    picture, if not present at diagnosis

51
Adult T-Cell Leukemia/Lymphoma
  • Japan
  • Median onset Mid 50s
  • Smoldering, indolent and acute forms occur
  • United States
  • Median onset in 30s
  • Most cases aggressive
  • Skin lesions hypercalcemia common

52
ATLL Treatment Survival
  • Treatment largely ineffective
  • Standard chemotherapy tolerated poorly
  • Treacherous due to immunocompromised state
  • Survival in U.S. poor
  • Median survival lt1 year

53
CLL Take Home Messages
  • CLL is a clonal proliferation of small,
    mature-appearing lymphocytes
  • It is common in the older population
  • Most cases are indolent, with long survival a
    minority are aggressive
  • It is incurable with conventional therapy
  • It is essentially the same as small lymphocytic
    lymphoma (SLL)

54
CLL Take Home Messages
  • Primary complications of CLL
  • Infections
  • Bone marrow suppression
  • Autoimmune diseases Autoimmune hemolytic anemia
  • Transformation to high grade lymphoma (Richter
    syndrome) Uncommon

55
CLL Take Home Messages
  • Treatment is palliative, not curative
  • Treatment indications
  • Bone marrow compromise
  • Bulky lymphadenopathy
  • Autoimmune phenomena
  • Lymphocytosis per se is not an indication for
    treatment

An older patient with stage 0 CLL (lymphocytosis
only) has normal life expectancy for age
56
Hairy Cell Leukemia Take Home Messages
  • Uncommon
  • Characteristic features
  • Pancytopenia
  • Circulating hairy lymphocytes
  • Splenomegaly, often massive
  • Positive TRAP stain
  • Effective therapy is available (Cladribine)

57
Adult T-Cell Leukemia/Lymphoma (ATLL) Take Home
Messages
  • Uncommon in U.S.
  • Common in Japan, parts of Caribbean
  • Caused by human T-cell lymphocytotrophic virus-1
    (HTLV-1)
  • Funny looking lymphocytes in blood
  • Lymph node, skin involvement
  • Aggressive course in U.S.
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