Transcript Systemic Lupus Erythematosus

Acute Myelogenous
Leukemia
Jim Czarnecki, D.O.
The First in a Four-Part Series
Introduction
Background


A malignant disease of the bone marrow in
which hematopoietic precursors are arrested in
an early stage of development.
Most AML subtypes are distinguished from
other related blood disorders by the presence of
more than 30% blasts in the blood, bone
marrow, or both.
Pathophysiology


Consists of a maturational arrest of bone
marrow cells in the early stages of development.
The mechanism is currently under investigation
and research, however it is known that it
involves the activation of abnormal genes
through chromosomal translocations and other
genetic abnormalities.
Pathophysiology

The developmental arrest results in 2 disease
processes:
A marked decrease in the production of normal
blood cells, resulting in varying degrees of anemia,
thrombocytopenia, and neutropenia.
 The rapid proliferation of these cells, along with a
reduction in their ability to undergo programmed
cell death. This results in their accumulation in
various organs, most commonly the liver and spleen.

Frequency


US: Estimates indicated that 10,100 new cases
would be diagnosed in 1999 (latest stat data).
Internationally: AML is more commonly
diagnosed in developed countries.
Mortality / Morbidity

In 1999, approximately 6,900 people in the US
died from AML.
With current chemotherapy regimens, approximately
25-30% of adults younger than 60 years survive
longer than 5 years and are considered cured.
 Results in older patients are more disappointing,
with fewer than 10% of patients surviving.

Race
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AML is more common in whites than in other
populations.
Sex
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AML is more common in men than in women.
Some researchers have proposed that the
increased prevalence of AML in men may be
related to occupational exposures.
Age
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Prevalence increases with age. The median age
of onset is 65 years.
However, this disease affects all age groups.
Clinical
History

Patients present with symptoms resulting from
bone marrow failure, organ infiltration with
leukemic cells, or both. The time course is
variable.
Some patients can present with acute symptoms over
a few days to 1-2 weeks
 Others have longer course, with fatigue or other
symptoms lasting from weeks to months.

History

Symptoms of bone marrow failure are related to
anemia, neutropenia, and thrombocytopenia.
The most common symptom is fatigue from the
anemia.
 Other symptoms from anemia include dyspnea upon
exertion, dizziness, and in patient with coronary
artery disease, anginal chest pain.
 In fact, myocardial infarction may be the first
presenting symptom of acute leukemia in the older
patient.

History

Patients often have decreased neutrophil levels
despite an increased total WBC count.
They present with fever, which may occur with or
without specific documentation of an infection.
 Patients often have a history of upper respiratory
infection symptoms that have not improved despite
appropriate oral antibiotic treatment.
 Patients present with bleeding gums and multiple
ecchymoses.

History
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Potentially life-threatening sites of bleeding include
the lungs, gastrointestinal tract, and the central
nervous system.
Symptoms may be the results of organ
infiltration with leukemic cells.
Most common sites include the spleen, liver, and
gums.
 Infiltration most commonly occurs in those patients
with monocytic subtypes of AML.

History
Patients with splenomegaly note fullness in the left
upper quadrant and early satiety.
 Patients with gum infiltration often present to their
dentist first. Gingivitis due to neuropenia can cause
swollen gums, and thrombocytopenia can cause the
gums to bleed.
 Patient’s with elevated WBC counts (> 100,000) can
present with symptoms of leukostasis (respiratory
and altered mental status). This is a medical
emergency.

Gum Hypertrophy
History

Patients with a high leukemic cell burden may
present with bone pain caused by increased pressure
in the bone marrow.
Physical
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Signs of anemia, include pallor and cardiac flow
murmur, are frequently present.
Fever and other signs of infection can occur,
including lung findings of pneumonia
Patients with thrombocytopenia usually
demonstrate petechiae, particularly on the lower
extremities
Physical
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Signs relating to organ infiltration with leukemic
cells include hepatosplenomegaly and, to a lesser
degree, lymphadenopathy.
Patients may have skin rashes due to infiltration
of the skin with leukemic cells (leukemia cutis).
Signs relating to leukostasis include respiratory
distress and altered mental status.
Leukemia Cutis
Causes

Although several factors have been implicated in
the causation of AML, most patients who
present with de novo AML have no identifiable
risk factor.
Causes

Antecedent hematologic disorders (AHD)
The most common is MDS – a disease of the bone
marrow of unknown etiology that occurs most often
in older patients and manifests as progressive
cytopenias that occur over months to years.
 Patients with low-risk MDS do not generally develop
AML.
 Other AHDs that predispose patients to AML
include aplastic anemia, myelofibrosis, paroxysmal
nocturnal hemoglobinuria, and polycythemia vera.

Causes

Congenital disorders
Usually, these patients will develop AML during
childhood; although rarely, some may present in
young adulthood.
 Disorders include Bloom syndrome, Down
syndrome, congenital neurtropenia, Fanconi anemia
and neurofibromatosis.

Causes
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Familial syndromes
Rare cases of familial erythroleukemia (a subtype of
AML), have been described.
 These families tend to present with a preleukemic
picture or acute leukemia in the sixth or seventh
decades.
 Inheritance appears to be autosomal dominant with
variable penetrance.

Causes
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Environmental exposures
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Several studies demonstrate a relationship between radiation
exposure and leukemia.
Early radiologists (prior to appropriate shielding) were found
to have an increased likelihood of developing anemia.
Patients receiving therapeutic irradiation for ankylosing
spondylitis were at increased risk.
Exposure to benzene is associated with aplastic anemia
andpancytopenia. These patients often develop AML.
Causes

Prior exposure to chemotherapeutic agents for
another malignancy.
Differentials
Differentials
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Acute Lymphoblastic Leukemia
Agnogenic Myeloid Metaplasia With
Myelofibrosis
Agranulocytosis
Anemia
Aplastic Anemia
Bone Marrow Failure
Differentials
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Chronic Myelogenous Leukemia
Lymphoma, B-Cell
Lymphoma, Lymphoblastic
Myelodysplastic Syndrome
Workup
Lab Studies

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CBC count with differential demonstrates
anemia. Patients with AML can have high,
normal, or low WBC counts.
Prothrombin time/fibrinogen products
Most common is DIC
 Acute promyelocytic leukemia (APL), also known as
M3, is the most common subtype of AML
associated with DIC.

Lab Studies

Peripheral blood smear
Review of peripheral blood smear confirms the
findings of the CBC count.
 Circulating blasts are usually seen.
 Schistocytes are occasionally seen if DIC is present.

Schistocytes
Schistocytes
Lab Studies

Chemistry profile
Most patients will have an elevated lactic
dehydrogenase level, and frequently, an elevated uric
acid level.
 Liver function tests and BUN/Creatinine level tests
are necessary prior to the initiation of therapy.
 Hypokalemia, hypocalcemia, hypomgnesemia may
develop because of renal losses seen in acute
monocytic leukemia (M5) and acute myelomonocytic
leukemia (M4).

Lab Studies
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Appropriate cultures should be obtained in
patients with fever or signs of infection, even in
the absence of fever.
Cytogenetic studies performed on bone marrow
provide important prognostic information and
are useful to confirm a diagnosis of APL.
Lab Studies

Bone marrow aspiration
This enables a blast count to be performed.
 Also allows an evaluation of the degree of dysplasia
in all cell lines and the number of platelet precursors
present
 The disease can then be classified into any of 7
subtypes (M1 – M7) based on cytochemical stains.

Imaging Studies
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Chest radiographics help assess for pneumonia
and signs of cardiac disease.
Multiple gated acquisition (MUGA) scan is
needed once the diagnosis is confirmed because
many of the chemotherapeutic agents used in
the treatment of AML are cardiotoxic.
Other Tests

Electrocardiography should be performed prior
to treatment.
Procedures
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Bone marrow aspiration and biopsy are the
definitive diagnostic tests.


Aspiration slides should be stained for morphology
with either Wright or Giemsa stain.
Bone marrow samples should also be sent for
cytogenetics testing and flow cytometry.
Histologic Findings
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M0 – Undifferentiated leukemia
M1 – Myeloblastic without differentiation
M2 – Myeloblastic with differentiation
M3 – Promyelocytic
M4 – Meylomonocytic

M4eo – Myelomonocytic with eosinophilia
Histologic Findings
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M5 – Monoblastic leukemia
M5a – Monoblastic without differentiation
 M5b – Monocytic with differentiation
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M6 – Erythroleukemia
M7 – Megakaryoblastic leukemia
Hematopoiesis
PLURIPOTENT
MIXED
STEM CELL PROGENITOR
CELL
COMMITTED
PROGENITOR
CELL
RECOGNIZABLE
BONE MARROW
PRECURSOR CELL
BFU-E/CFU-E
CFU-Eos
red cell
neutrophil
monocyte
eosinophil
CFU-Baso
basophil
CFU-GM
myeloid
progenitor
cell
pluripotent
stem cell
lymphoid
progenitor
cell
pronormoblast
myeloblast
monoblast
MATURE
BLOOD
CELL
CFU-Meg
megakaryocyte
platelet
pre-T
lymphoblast
T-cell
pre-B
lymphoblast
B-cell
& plasma cell
Myeloid Maturation
myeloblast promyelocyte
myelocyte
metamyelocyte
MATURATION
band
neutrophil
Acute Myelogenous Leukemia
Acute Myelogenous Leukemia
Acute Myelogenous Leukemia
AML – Auer Rods
Treatment
Medical Care
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Current standard chemotherapy regimens cure
only a minority of patients.
As a result, all patients should be evaluated for
entry into well-designed clinical trials.
If a clinical trial is not available, patients can be
treated with standard therapy.
Induction Therapy
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Does not treat acute promyelocytic leukemia
Most common approach is “3 and 7”, which is 3
days of a 15- to 30-minute infusion of an
anthracycline (idarubicin or daunorubicin) or
anthracenedione (mitoxantrone) combined with
arabinosylcytosine (araC), 100 mg/m2 as a 24hour infusion daily for 7 days.
Induction Therapy

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Idarubicin is given at a dose of 12 mg/m2/d for 3 days,
daunorubicin at 45-60 mg/m2/d for 3 days, or
mitoxantrone at 12 mg/m2/d for 3 days.
These regimens require adequate cardiac, hepatic, and
renal function.
Using these regimens, approximately 50% of patients
achieve remission with one course. Another 10-15%
enter remission following a second course of therapy.
Consolidation Therapy


In order to define the best post-remission
therapy for young patients, several large,
randomized studies comparing allogeneic bone
marrow transplant (BMT), autologous BMT, and
chemotherapy without BMT have been
performed.
Unfortunately, the results of the studies are
conflicting.
Consolidation Therapy
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The following recommendations can be
followed:

Patients with good-risk AML, and inversion of
chromosome 16, have a good prognosis following
consolidation with high-dose araC and should be
offered such therapy. Transplantation should be
reserved for patients who relapse.
Consolidation Therapy
Patient’s with high-risk cytogenetics findings are
rarely cured with chemotherapy and should be
offered transplantation in first remission
 However these patients are also at high risk for
relapse following transplantation.

Consolidation Therapy
The best approach for patients with intermediaterisk cytogenetics findings is controversial.
 Some oncologists refer patients for transplantation
in first remission, whereas others give consolidation
chemotherapy with high-dose araC for 4 courses and
reserve transplantation for patient who relapse.

Consolidation Therapy

For older patients:
The best post-remission therapy for elderly patients
has yet to be determined.
 Most patients are ineligible for standard allogeneic
BMT.
 Some patients may be candidates for autologous
BMT; however, the effectiveness of autologous
BMT in this patient population is unclear.

Consolidation Therapy
The most commonly used regimen is araC at 100
mg/m2 daily for 5 days combined with 2 days of
anthracycline, for 2 courses.
 Newer approaches under investigation include
monoclonal antibodies and allogeneic transplantaion
following nonmyeloablative chemotherapy
(minitransplants).

Relapsed AML
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Patients with relapsed AML have an extremely
poor prognosis.
Most patients should be referred for
investigational therapies.
Supportive Care

Replacement of blood products
Patients with AML have a deficiency in the
production of normal blood cells, therefore need
replacement. All blood products should be irradiated
to prevent graft-versus-host disease, which is almost
invariably fatal.
 PRBCs are given to patients with a hemoglobin level
of less than 7-8 g/dL, or at a higher level if the
patient has cardiovascular or respiratory
compromise.

Supportive Care
Platelets should be transfused if the level is less than
10,000 to 20,000 cells/uL.
 Fresh frozen plasma should be given to patients with
a significantly prolonged prothrombin time, and
cryoprecipitate should be given if the fibrinogen
level is less than 100 g/dL.

Supportive Care

Antibiotics
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Should be given to all febrile patients.
At minimum, should include broad-spectrum coverage, such
as a third-generation cephalosporin, usually with an
aminoglycoside.
For patients receiving antibiotics with persistant fever of no
focus, should also receive amphotericin at a dose of 0.5
mg/kg.
Allopurinol at 300 mg should be given 1-3 times a day during
induction therapy until clearance of blasts and resolution of
hyperuricemia.
Follow-up
Further Inpatient Care

Patients require readmission for consolidation
therapy or for the management of toxic effects
of chemotherapy.
Further Outpatient Care

Patients should come to the office for
monitoring of disease status and chemotherapy
effects.
Deterrence / Prevention

While receiving chemotherapy, patients should
avoid exposure to crowds and people with
contagious illnesses, especially children with viral
infections.
Complications


The most common complication is failure of
the leukemia to respond to chemotherapy.
The prognosis for these patients is poor because
they usually do not respond to other
chemotherapy regimens.
Prognosis

Relies on several factors:
Increasing age is an adverse factor because older
patients more frequently have cormorbid medical
conditions that compromise the ability to give full
doses of chemotherapy.
 Cytogenetic analysis of the bone marrow is one of
the most important prognostic factors. Patients with
t(8;21), t(15;17) or inversion 16 have the best
prognosis, with long-term survival rates of
approximately 65%.

Patient Education

Patients should be instructed to call immediately
if they are febrile or have signs of bleeding.
Competency Exam
Question One
1) Acute Myelogenous Leukemia (AML) is defined
as:
A) 5% blasts in bone marrow
B) 12% blasts in bone marrow
C) 25% blasts in bone marrow
D) 30% blasts in bone marrow
E) 75%+ blasts in bone marrow
Question One
1) Acute Myelogenous Leukemia (AML) is defined
as:
A) 5% blasts in bone marrow
B) 12% blasts in bone marrow
C) 25% blasts in bone marrow
D) 30% blasts in bone marrow
E) 75%+ blasts in bone marrow
Question Two
2) All of the following cytogenetic analysis
indicators have the best prognosis, except:
A) t(8;21)
B) t(15;17)
C) Inversion 16
D) 11q23
Question Two
2) All of the following cytogenetic analysis
indicators have the best prognosis, except:
A) t(8;21)
B) t(15;17)
C) Inversion 16
D) 11q23
Question Three
3) Acute promyelocytic leukemia can be treated
with induction therapy, as well as combination
therapy.
A) True
B) False
Question Three
3) Acute promyelocytic leukemia can be treated
with induction therapy, as well as combination
therapy.
A) True
B) False
End of Lecture
Thank you for your attendance.
This lecture will be made available at
the Internal Medicine Residency
website:
http://IM.official.ws