Chronic leukemias

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
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
Philadelphia chromosome
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.
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
(>30% 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
Chronic leukemias
 Bleeding, petechiae, ecchymoses from abnormal
platlets
 Lab features
 Leukocytosis and anemia; ¾ have WBC counts> 100
x 109/L
 Normal appearing granulocytes at all stages of
maturation are seen in the peripheral smear (they
are not functionally normal, however); < 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)
CML
CML – abnormal platlet
CML – blast transformation
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
Chronic leukemias
 Eosinophilic leukemia
 Is this a distinct entity or a variant of CML?
 30-70% eosinophils with a WBC count > 30 x
109/L and a shift to the left
 The prognosis is poor with a median survival of <
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
Chronic leukemias
 Chronic lymphocytic leukemia
 This is predominantly a disease of the elderly; >
90% are over 50 and 2/3 are over 60; male:female
is 2:1
 Is characterized by peripheral and bone marrow
lymphocytosis and a survival of a few years to > 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
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 > 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
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
CLL with smudge cells
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 < 3 areas of lymphoid
involvement (lymph nodes, spleen, liver)
 Stage B – same as A, but > 3 areas of
lymphoid involvement
 Stage C – lymphocytosis with anemia,
thrombocytopenia, or both
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
Chronic leukemias
 Differential diagnosis
 Must distinguish between CLL and prolymphocytic
leukemia, hairy cell leukemia, large, granular
lymphocyte leukemia, Sezary’s syndrome, and
circulating lymphoma cells
 Prolymphocyte leukemia
 This is an aggressive leukemic disorder of mature B or T
cells
 > 55% of the lymphocytes are prolymphocytes which are
large with moderate amounts of pale basophilic cytoplasm,
mature condensed chromatin, and a single prominent
nucleolus
Prolymphocytic leukemia
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
Hairy cell leukemia
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 > 10 years
 Sezary’s 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
Large, granular lymphocyte
leukemia
Sezary’s syndrome
Chronic leukemias
 Circulating lymphoma cells
 Patients with non-Hodgkins lymphoma may develop
peripheral blood involvement