Transcript 19. Leukemia_

Leukemia
Copyright, 1996 © Dale Carnegie & Associates, Inc.
Leukemia
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Leukaemias are malignant disorders of the
haematopoietic stem cell compartment,
characteristically associated with increased
numbers of white cells in the bone marrow
and/or peripheral blood. The course of
leukaemia may vary from a few days or weeks
to many years, depending on the type.
4 main types of leukemia
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Acute or chronic
Myeloid or Lymphocytic
Demographics of Leukemia
Patients
CLL=Chronic
Lymphocytic
ALL
11%
others
17%
ALL=Acute
Lymphocytic
CML=Chronic
Mylogenous
AML=Acute
Mylogenous
CML
15%
CLL
26%
AML
31%
Stem cells and growth factors in
haematopoietic cell development.
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page 1003
Hematopoietic stem cells give rise to two major
progenitor cell lineages, myeloid and lymphoid
progenitors
Leukemia Development

The development of Leukemia
 uncontrolled and accelerated production of
haematopoietic stem cell, progenitors, or
mature blood cells which results in incomplete
or defective cell maturation
ALL
CLL
Lymphomas
MM
naïve
B-lymphocytes
Lymphoid
progenitor
AML
Hematopoietic
stem cell
Myeloid
progenitor
Plasma
cells
T-lymphocytes
Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Main Types
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Acute Lymphocytic Leukemia (ALL)
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Acute Mylogenous Leukemia (AML)
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Chronic Lymphocytic Leukemia (CLL)
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Chronic Mylogenous Leukemia (CML)
Acute leukemia
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is characterized by a rapid increase in the numbers
of immature blood cells. Crowding due to such
cells makes the bone marrow unable to produce
healthy blood cells. Immediate treatment is
required in acute leukemia due to the rapid
progression and accumulation of the malignant
cells, which then spill over into the bloodstream
and spread to other organs of the body. Acute
forms of leukemia are the most common forms of
leukemia in children.
Chronic leukemia
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is characterized by the excessive build up of relatively
mature, but still abnormal, white blood cells. Typically
taking months or years to progress, the cells are produced
at a much higher rate than normal cells, resulting in many
abnormal white blood cells in the blood. Whereas acute
leukemia must be treated immediately, chronic forms are
sometimes monitored for some time before treatment to
ensure maximum effectiveness of therapy. Chronic
leukemia mostly occurs in older people, but can
theoretically occur in any age group.
Pathophysiology
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Malignant transformation usually occurs at
the pluripotent stem cell level, although it
sometimes involves a committed stem cell
with more limited capacity for
differentiation. Abnormal proliferation, clonal
expansion, and diminished apoptosis
(programmed cell death) lead to
replacement of normal blood elements with
malignant cells.
Main Signs and symptoms
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1. Hyperplasia or hyperproliferation of
affected cell - uncontrolled proliferation of
malignant cells and their spreading (in bone
marrow, peripheral blood and organ
infiltration (spleen (nausea or feeling of
fullness due to an enlarged liver and
spleen), lymph nodes, skin, gastrointestinal
tract, central nervous system (neurological
symptoms (headaches)).
Main Signs and symptom
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2. Malignant cells replace normal bone marrow elements
leading to
a) anemia (clinical manifestation - dyspnea and pallor),
b) thrombocytopenia (people with leukemia may easily
become bruised, bleed excessively, or develop pinprick
bleeds (petechiae),
c) neutropenia (clinical manifestation - frequent infection,
ranging from infected tonsils, sores in the mouth, or
diarrhea to life-threatening pneumonia or opportunistic
infections),
Main Signs and symptom
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3. Nonspecific symptoms of intoxication (feeling
sick, such as having fevers, chills, night sweats and
other flu-like symptoms, or feeling fatigued),
4. Metabolic and Electrolyte Abnormalities
Pictures Of Blood
Platelet
Red Cell
White Cell
Platelet
White Cell
Blasts
Red Cell
Normal human blood
Blood with leukemia
Development of Leukemia in
the Bloodstream
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Legend
White Cell
Red Cell
Platelet
Blast
Germ
Stage 5a- Anemia
Stage 4- Worsening
Sources from Leukemia, by D. Newton and D. Siegel
Stage 5b- Infection
ACUTE LEUKEMIA
DEFINITION
Acute leukemias are clonal malignant
hematopoietic disorders resulting from genetic
alterations in normal hematopoietic stem cells.
These alterations disrupt normal differentiation
and/or cause excessive proliferation of
abnormal immature “leukemic” cells or
“blasts.” As the disease progresses, leukemic
cells accumulate in the bone marrow, blood, and
organs, displacing normal progenitor cells and
suppressing normal hematopoiesis.
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Clinical presentation
Common symptoms of both acute myeloid leukemia
(AML) and acute lymphoblastic leukemia (ALL) are
a reflection of bone marrow failure and include
fatigue, bruising or bleeding, fever, and infection.
 Pancytopenia:
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WBCinfection.
Hb anemia.
platelets bleeding.
Organ infiltration:
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Lymphadenopathy.
Splenomegally.
Hepatomegally.
CNS: 5-10% of patient with ALL
Investigations:
CBC:
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60% of pts have an elevated WBC.
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Most are anemic
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Most are thrombocytopenic
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90% have blast in the periphral blood film.
electrolytes:
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Hypo/hyper kalemia
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Hypomagnesimia
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hyperphosphatemia
Hypermetabolism:
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LDH.
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uric acid.
DIC:
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Most common with promyelocytic leukemia, small% monocytic leukemia
& ALL
Bone marrow biopsy and aspirate:
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30%or more of all nucleated cells are blast.
Radiology:
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CXR: mediastinal mass(T-cell ALL)
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Osteopenia or lytic lesion 50% of patients with ALL.(itractable pain).
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Acute leukemia diagnostic algorithm.
French-American-British (FAB) Classification
of Acute Myelogenous Leukemia
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M0 AML with no Romanowsky or cytochemical evidence of differentiation
M1 Myeloblastic leukemia with little maturation
M2 Myeloblastic leukemia with maturation
M3 Acute promyelocytic leukemia (APL)
M3h APL, hypergranular variant
M3v APL, microgranular variant
M4 Acute myelomonocytic leukemia (AMML)
M4eo AMML with dysplastic marrow eosinophils
M5 Acute monoblastic leukemia (AMoL)
M5a AMoL, poorly differentiated
M5b AMoL, differentiated
M6 “Erythroleukemia”
M6a AML with erythroid dysplasia
M6b Erythroleukemia
M7 Acute megakaryoblastic leukemia (AMkL)
Lymphoblast/myeloblast
Acute lymphoblastic leukemia
ALL-L1
Acute lymphoblastic leukemia
ALL-L1
Acute lymphocytic leukemia ALLL2
Acute lymphocytic leukemia ALLL3
Acute lymphocytic leukemia ALLL3
Acute myeloid leukemia AML-M0
Acute myeloid leukemia AML-M1
Acute myeloid leukemia AML-M2
Acute myeloid leukemia AML-M2
+ peroxidase
Acute myeloid leukemia AML-M3
Acute myeloid leukemia AML-M3
hypogranular
Acute myeloid leukemia AML-M4
Acute myeloid leukemia AML-M5
Acute myeloid leukemia AML-M6
Acute myeloid leukemia AML-M7
Management:
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A-Supportive measure:
-isolation in positive laminer flux room
-insertion of central line
-family and patient support by permanent social
worker
-AlKaline diuresis to prevent tumor lysis syndrome
-oropharynx/GIT decontamination to prevent fungal
infection
-IV antibiotics for infection
-Blood transfusion if anemia and thrombocytopenia.
Cont:
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Special consideration:
CNS:
-neuroprophylaxis:
by intrathecal chemotherapy, high dose
systemic MTX or Aracytine. OR
cerebrospinal irradiation
- meningeal infiltration:
Testis:
or chidectomy/radiotherapy if testis involvement.
Prognosis in ALL
parameters
Good
poor
WBC
low
High(>50x10 9 /l)
Gender
Girls
Boys
Immunophenotype
C-ALL
B-ALL
Age
Child
Adult or infant.
Cytogenetic
Normal,hyperdiploid,
Ph+,11q23rearrangements.
Time to clear blast
from blood
< 1week
>1week
Time to remission
<4weeks
>4weeks
Cns disease at
presentation
Absent
Present
Minimal residual
disease.
Negative at 1-3 months
Still positive at 3-6 months.
Prognosis in AML
parameters
Cytogentics
BM response to
remission induction
age
Favorable
unfavorable
T(15;17).
T(8;21).
Inv(16).
Deletion of
chromosome5or7.
11q23
T(6;9)
Abn(3q)complex
rearrangments
<5% blasts after first
course
>20% blasts after first
course.
<60yrs
>60yrs
Chronic lymphocytic leukemia (1)
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Is characterised by the accumulation of
nonproliferating mature-appearing
lymphocytes in the blood, marrow, lymph
nodes, and spleen
In most cases, the cells are monoclonal B
lymphocytes that are CD5+
T cell CLL can occur rarely
CLINICAL
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Localized or generalized
lymphadenopathy
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Splenomegaly (30-40% of cases)
Hepatomegaly (20% of cases)
Petechiae
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Pallor
lymphadenopathy
Chronic lymphocytic leukemia
Hairy-cell leukemia
Smudge Cells
Smudge Cells
The diagnostic criteria for CLL
1) A peripheral blood lymphocyte count of
greater than 5 G/L, with less than 55% of
the cells being atypical
2) The cell should have the presence of Bcellspecific differentiation antigens (CD19,
CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater
than 30% lymphocytes
Investigations
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Pretreatment studies of patients with CLL should
include examination of:
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complete blood count
peripheral blood smear
reticulocyte count
Coomb’s test
renal and liver function tests
serum protein electrophoresis
immunoglobulin levels
plasma 2 microglobulin level
If available immunophenotyping should be carried
out to confirm the diagnosis
Bone marrow biopsy and cytogenetic analysis is not
routinely performed in CLL
Staging (1)
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Rai Classification for CLL
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0 - lymphocytosis (>5 G/L)
I - lymphocytosis + lymphadenopathy
II - lymphocytosis + splenomegaly +/-lymphadenopathy
III - lymphocytosis + anemia (Hb <11g%) +/lymphadenopathy or splenomegaly
IV - lymphocytosis + thrombocytophenia (Plt <100G/L)
+/- anemia +/-lymphadenopathy +/- splenomegaly
Staging (2)
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Binet Classification for CLL
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A. < 3 involved areas, Hb > 10g%, Plt > 100G/L
B. > 3 involved areas, Hb > 10g%, Plt > 100G/L
C. - any number of involved areas, Hb < 10g%,
Plt < 100G/L
Prognosis
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Rai classification
stage
0
I
II
III
IV
median survival
(years)
>10
> 8
6
2
< 2
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Binet classification
stage
A
B
C
median survival
(years)
> 10
7
2
Treatment
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Treatment is reserved for patients with low- or
intermediate risk disease who are symptomatic or
have progressive disease (increasing organomegaly
or lymphocyte doubling time of less than 12
months) and patients with high -risk disease
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Alkylating agents (chlorambucil, cyclophosphamide)
Nucleoside analogs (cladribine, fludarabine)
Biological response modifiers
Monoclonal antibodies
Bone marrow transplantation
And systemic complications requiring therapy
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antibiotics
immunoglobulin
steroids
blood products
Chronic Myeloid Leukemia
Chronic myelogenous
leukemia
(CML) is a myeloproliferative disorder characterized by
increased proliferation of the granulocytic cell line
without the loss of their capacity to differentiate.
Consequently, the peripheral blood cell profile shows
an increased number of granulocytes and their
immature precursors, including occasional blast cells.
Chronic myeloid leukemia
Leukemia
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Chronic Myelogenous Leukemia
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Cancer of the granulocytes or
monocytes, compared to
leukocytes in lymphocytic
leukemia
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Comprises about 14% of all
adult leukemias
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Males slightly higher than
females
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One of the first cancers to
have a specific genetic link to
a chromosomal mutation
identified for the disease
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Philadelphia Chromosome
Pathophysiology
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Disorder of the stem cells in
bone marrow
General infection fighting cells
are the most harmed >
granulocytes and monocytes
(aka, neutrophils)
These immature cells take over
the body’s mature neutrophils
and hinder the body’s ability to
fight infection properly
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CML is caused by a genetic
mutation with chromosomes 9
and 22 in the body
Abl on chromosome 9 is
translocated to chromosome 22
and fuses with Bcr
This ABL-BCR protein is an
unregulated tyrosine kinase and
thus, is the source of the
reproduction of immature
granulocytes
Other functions include:
upstream changes of DNA
repair mechanisms, suppression
of the body’s programmed cell
death proteins, and changes in
cytoskeletal structures
HEPATOSPLENOMEGALY
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The disease has 3 clinical phases, and it
follows a typical course of an initial
chronic phase, in which the disease
process is easily controlled; followed by
a transitional and unstable course
(accelerated phase); and, finally, a
more aggressive course (blast crisis),
which usually is fatal.
Accelerated phase
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which may last for several months. The survival of patients
diagnosed in this phase is 1-1.5 years. This phase is
characterized by poor control of the blood counts with
myelosuppressive medication and the appearance of
peripheral blast cells ( 15%), promyelocytes ( 30%),
basophils ( 20%), and platelet counts less than 100,000
cells/ L unrelated to therapy. The doses of the
medications need to be increased; splenomegaly may not
be controllable by medications, and anemia can worsen.
Bone pain and fever, as well as an increase in bone
marrow fibrosis, are harbingers of the last phase.
Acute phase, or blast crisis,
o
is similar to acute leukemia, and survival is 3-6
months at this stage. Bone marrow and
peripheral blood blasts of 30% or more are
characteristic. Skin or tissue infiltration also
defines blast crisis. Cytogenetic evidence of
another Ph-positive clone (double) or clonal
evolution (other cytogenetic abnormalities such
as trisomy 8, 9, 19, or 21, isochromosome 17, or
deletion of Y chromosome) usually is present.
blast crisis
Treatment Options:
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Pharmacotherapy
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Newer drugs are
prolonging chronic phase
and increasing the
number of patients who
enter into remission
They are easier on the
body versus SCT
Old Standard:
hydroxyurea (no possible
cytogenic response) or
interferon alpha +
cytarabine
New Standard: tyrosine
kinase inhibitors
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Imatinib, dasatanib,
nilotonib
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Stem Cell Transplant
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Using bone marrow from
a donor to “resupply” the
patient
Can be the only
“curative” measure,
although many
drawbacks
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Must be good
candidates for surgery
Must have a relatively
short time from
diagnosis to transplant
Matching donor
Possible relapse of CML
Rejection (GVHD)
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A small number of patients
show some resistance to
Imatanib
The BRC-ABL transcript has
the ability to mutate and thus
make imatinib ineffective
Imatinib binds to the closed
conformation and BRC-ABL can
mutate to the open
conformation and thus makes
imatanib ineffective
Two 2nd generation TKIs have
proven to be more potent and
are in trials to determine
effectiveness against
resistance to imatanib
Treatment Algorithm