Chronic leukemias

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Chronic leukemias
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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

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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

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Philadelphia chromosome
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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.

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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

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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)

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CML
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CML abnormal platlet
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CML blast transformation
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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

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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

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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

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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

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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

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CLL with smudge cells
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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

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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

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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

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Prolymphocytic leukemia
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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

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Hairy cell leukemia
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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

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Large, granular lymphocyte leukemia
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Sezarys syndrome
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Chronic leukemias

• Circulating lymphoma cells
• Patients with non-Hodgkins lymphoma may develop
  peripheral blood involvement