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Chronic leukemias

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Chronic leukemias Chronic leukemias Chronic myelogenous (granulocytic) leukemia Is characterized by an unregulated proliferation of myeloid elements in the bone ... – PowerPoint PPT presentation

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Title: Chronic leukemias


1
Chronic leukemias
2
Chronic leukemias
  • Chronic myelogenous (granulocytic) leukemia
  • Is characterized by an unregulated proliferation
    of myeloid elements in the bone marrow, liver and
    spleen, leading to marked leukocytosis and
    organomegaly.
  • Incidence
  • 20 of all leukemias
  • Primarily affects adults 25-60 years old, with a
    peak incidence at 40-59.
  • Etiology, pathogenesis and physiology
  • May occur after anything that can induce
    chromosomal aberrations such as ionizing
    radiation, alkylating agents, and exposure to
    other biologically active chemicals

3
Chronic leukemias
  • Appears to be a clonal hematopoietic stem cell
    disorder
  • 90 of CML have a Philadelphia (Ph) chromosome
    (reciprocal translocation between chromosome 22
    and chromosome 9) by cytogenetic karyotype
    studies. A BCR/ABL hybrid gene is created. The
    gene product has enhanced tyrosine kinase
    activity that results in
  • Increased granulocyte-colony stimulating factor
  • Increased platlet derived growth factor
  • Suppression of apoptosis in hematopoietic cells
  • The remaining 5-10 are positive for the
    translocation using more sensitive DNA studies
    such as RT-PCR or fluorescent in situ
    hybridization
  • The Ph chromosome is found in all hematopoietic
    cells except T lymphocytes (and sometimes B
    lymphocytes)
  • The Ph cells have a growth advantage over normal
    cells

4
Philadelphia chromosome
5
Chronic leukemias
  • The progeny of the original malignant cell, after
    2-6 years, eventually replace the normal
    hematopoietic elements and become the prominent
    cell
  • By the time the disease becomes clinically
    evident, nearly all the myeloid cells in the bone
    marrow are Ph
  • As the disease progresses, the Ph cells
    undergo additional chromosomal aberrations and
    the patients ultimately terminate in a blast
    crisis.
  • The clinical course of the disease occurs in
    three stages
  • Asymptomatic, proliferative stage Ph cells
    appear in the bone marrow and the peripheral
    leukocyte count is normal
  • The symptomatic, chronic stage occurs after about
    6.3 years at this stage the peripheral
    leukocyte count is increased and immature
    granulocytes appear in the peripheral blood.

6
Chronic leukemias
  • The hyperproliferation is easily controlled with
    chemotherapy, but the remission is only temporary
    and patients still have Ph cells in the bone
    marrow.
  • Accelerated or acute stage this is also called
    a blast crisis (gt30 blasts in the bone marrow)
  • Cellular proliferation is uncontrollable and
    resembles AML.
  • The medium survival is 10 weeks
  • Signs and symptoms
  • Malaise
  • Fatigue due to anemia
  • Fever
  • Weight loss
  • Sweating
  • Bone aches and fullness in upper abdomen due to
    expansion of the bone marrow and organomegaly

7
Chronic leukemias
  • Bleeding, petechiae, ecchymoses from abnormal
    platlets
  • Lab features
  • Leukocytosis and anemia ¾ have WBC countsgt 100 x
    109/L
  • Normal appearing granulocytes at all stages of
    maturation are seen in the peripheral smear (they
    are not functionally normal, however) lt 10 are
    blasts and promyelocytes
  • Many have a thrombocytosis with variation in
    shape platlet function is frequently abnormal
  • Low to absent leukocyte alkaline phosphatase
    activity (Low LAP score)

8
CML
9
CML abnormal platlet
10
CML blast transformation
11
Chronic leukemias
  • Treatment
  • Median survival from the time of diagnosis used
    to be 3 years
  • The prognosis is better if the WBC count is lower
    and the of blasts is low
  • Chemotherapy with a single agent has been used
    and 75 in the chronic phase of the disease go
    into remission. However, Ph cells remain in
    the bone marrow
  • Bone marrow transplants during the chronic phase
    (high dose chemo/radiotherapy followed by
    infusion of normal, compatible bone marrow) used
    to be the best therapy
  • A new drug, Gleevec, is now available and it
    specifically targets the BCR/ABL gene product.
    The Ph cells are destroyed, while normal cells
    are unaffected

12
Chronic leukemias
  • Eosinophilic leukemia
  • Is this a distinct entity or a variant of CML?
  • 30-70 eosinophils with a WBC count gt 30 x 109/L
    and a shift to the left
  • The prognosis is poor with a median survival of lt
    1 year
  • Basophilic leukemia
  • Is this a distinct entity or a variant of CML?
  • Is extremely rare with 40-80 basophils and a
    left shift

13
Chronic leukemias
  • Chronic lymphocytic leukemia
  • This is predominantly a disease of the elderly gt
    90 are over 50 and 2/3 are over 60 malefemale
    is 21
  • Is characterized by peripheral and bone marrow
    lymphocytosis and a survival of a few years to gt
    10 years
  • This is a B cell abnormality
  • The lymphocytes appear normal, but are
    immunologically incompetent. However, some
    functionally normal B cells remain and there is a
    normal T cell pool

14
Chronic leukemias
  • Etiology
  • Genetic factors are important since it runs in
    families
  • Clinical course
  • The pace of the disease varies and is dependent
    on the rate of accumulation of abnormal
    lymphocytes
  • Median survival is 3-4 years, but 10-15 survive
    gt 10years
  • There is no tendency for blast transformation,
    but complications of advanced disease result from
    progressive accumulation of long-lived, poorly
    functional lymphocytes.
  • Signs and symptoms
  • Organomegaly and lymphadenopathy
  • Often discovered accidentally
  • Fatigue

15
Chronic leukemias
  • Near the end bruising, pallor, fever, and
    weight loss
  • Lab features
  • Absolute lymphocytosis of 10-150 x 109/L
  • Lymphocytes usually appear normal, but they are
    markedly fragile and smudge cells are seen on the
    peripheral smear
  • It is not necessary to do a bone marrow biopsy
    for diagnosis.
  • Anemia occurs late in the disease and may be due
    to decreased production secondary to marrow
    infiltration, hypersplenism, or autoimmune
    hemolytic anemia the same things may cause
    neutropenia or thrombocytopenia
  • Hypogammaglobulinemia as the disease progresses

16
CLL with smudge cells
17
Chronic leukemias
  • Prognosis is related to the extent and
    distribution of the disease also called the
    stage
  • Stage A lymphocytosis without anemia or
    thrombocytopenia and lt 3 areas of lymphoid
    involvement (lymph nodes, spleen, liver)
  • Stage B same as A, but gt 3 areas of lymphoid
    involvement
  • Stage C lymphocytosis with anemia,
    thrombocytopenia, or both

18
Chronic leukemias
  • Treatment
  • Stage A observe only
  • Stage B with no symptoms same as A
  • Stage B with symptoms - therapeutic intervention
    to relieve signs and symptoms
  • Stage C - therapeutic intervention to relieve
    signs and symptoms
  • The goal of therapy is simply to relieve signs
    and symptoms

19
Chronic leukemias
  • Differential diagnosis
  • Must distinguish between CLL and prolymphocytic
    leukemia, hairy cell leukemia, large, granular
    lymphocyte leukemia, Sezarys syndrome, and
    circulating lymphoma cells
  • Prolymphocyte leukemia
  • This is an aggressive leukemic disorder of mature
    B or T cells
  • gt 55 of the lymphocytes are prolymphocytes which
    are large with moderate amounts of pale
    basophilic cytoplasm, mature condensed chromatin,
    and a single prominent nucleolus

20
Prolymphocytic leukemia
21
Chronic leukemias
  • Hairy cell leukemia
  • This is mainly a disease of elderly men
  • Patients present with marked splenomegaly, but
    not lymphadenopathy
  • Patients have fatigue and malaise
  • Pancytopenia
  • The peripheral smear shows atypical mononuclear
    lymphocytoid cells with hairy projections on
    their surfaces
  • The bone marrow yields a dry tap because the
    malignant cells are often surrounded by fibrosis
  • Splenectomy and interferon as well as new
    chemotherapeutic drugs are successful in
    promoting long lasting remissions

22
Hairy cell leukemia
23
Chronic leukemias
  • Large, granular lymphocyte leukemia
  • T cell or NK cell in origin
  • Is characterized by a moderate lymphocytosis
    composed of cells with abundant pale-staining
    cytoplasm and nuclei with mature, clumped
    chromatin
  • Anemia is common, but neutropenia is rare
  • Most patients survive gt 10 years
  • Sezarys syndrome
  • Occurs in patients with cutaneous T cell lymphoma
  • The lymphocytes seen in the peripheral smear
    have a very large, convoluted nuclear outline and
    finely distributed chromatin

24
Large, granular lymphocyte leukemia
25
Sezarys syndrome
26
Chronic leukemias
  • Circulating lymphoma cells
  • Patients with non-Hodgkins lymphoma may develop
    peripheral blood involvement
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