Acute Myelogenous Leukemia

DEFINITION. Acute myelogenous leukemia (AML) is a

malignant disease of the bone marrow in which hematopoietic
precursors are arrested in an early stage of development.
BLASTS in b.m.: >20%

PATHOPHYSIOLOGY
AML=maturational arrest of bone marrow cells in the earliest
stages of development.

CONSEQUENTLY: 2 disease processes:

-First, the production of normal blood cells markedly decreases,
which results in varying degrees of anemia, thrombocytopenia, and
neutropenia.
- Second, the rapid proliferation of these cells, along with a reduction
in their ability to undergo programmed cell death (apoptosis), results in
their accumulation in the bone marrow, blood, and, frequently, the
spleen and liver.

FREQUENCY: 3/100.000 annually

Acute myelogenous leukemia (AML) is more commonly diagnosed in developed
countries.
RACE
Acute myelogenous leukemia (AML) is more common in whites than in other
populations.
SEX : AML is more common in women .
AGE: The prevalence of acute myelogenous leukemia (AML) increases with age.

ETIOLOGY:

-IDIOPATHIC;
-CAUSES:
1. Antecedent hematologic disorders:

-MDS.
- APLASTIC ANEMIA
-MYELOFIBROSIS
-PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

2. Congenital disorders
-Down syndrome,
-congenital neutropenia,
-Fanconi anemia,
-neurofibromatosis.
-Familial syndromes

3. Environmental exposures :

-IRRADIATION (professional, accidental, therapeutic)

-Persons who smoke have a small but statistically significant (odds ratio, 1.5)
increased risk of developing myelogenous leukemia (AML). In several studies,
the risk of AML was slightly increased in people who smoked compared with
those who did not smoke.

-BENZENE : aplastic anemia and pancytopenia. These patients often develop

AML. Many of these patients demonstrate M6 morphology.

-CHEMOTHERAPY
(3-5 ys or 9-12 months,according to agents)
CLINICAL

-SYMPTOMS RESULT FROM:

1.-BONE MARROW FAILURE:

ANEMIA + NEUTROPENIA + THROMBOCYTOPENIA

ANEMIA + INFECTIONS + HEMORRHAGIA

ANEMIA:
-FATIGUE
-EXERTIONAL DYSPNEA
-DIZINESS
-ANGINAL CHEST PAIN….MYOCARDIAL INFARCTION

NEUTROPENIA:
-INFECTIONS
…UPPER RESPIRATORY INFECTIONS RESISTANT TO ANTIBIOTICS…

THROMBOCYTOPENIA:
-BLEEDING GUMS
-ECCHYMOSES
-DISSEMINATERD INTRAVASCULAR COAGULATION

2-ORGAN INFILTRATION WITH LEUKEMIC CELLS

-LIVER, SPLEEN, SKIN, GUMS;

-LEUKOSTASIS
-BONE PAIN
-LYMPH NODES ENLARGEMENT

.
LABORATORY
- CBC count with differential:
anemia
thrombocytopenia
WBC: normal, decreased , elevated value.
Circulating blasts are usually seen.
-coagulogram : DIC (if present), schyzocytes
Chemistry profile:
-elevated lactic dehydrogenase (LDH) level and, frequently,
-elevated uric acid level.
-Liver function tests
-blood urea nitrogen (BUN)/creatinine

Appropriate cultures should be obtained in patients with fever or signs of infection, even
in the absence of fever.

Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential
candidates for allogeneic transplantation.

Bone marrow aspiration

AML is defined as the presence of greater than 20% blasts in the marrow.

The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell
lines.
Bone marrow biopsy is useful to assess cellularity. Biopsy is most
important in patients in whom an aspirate can not be obtained (dry tap).

Flow cytometry (immunophenotyping) can be used to help distinguish acute

myelogenous leukemia (AML) from acute lymphocytic leukemia (ALL) and further
classify the subtype of AML. The immunophenotype correlates with prognosis in some
instances.
Cytogenetic studies performed on bone marrow provide important prognostic
information and are useful to confirm a diagnosis of APL, which bears the t(15;17)
chromosome abnormality and is treated differently.
Fluorescence in situ hybridization (FISH) studies can be
used to get a faster overview of cytogenetic abnormalities than traditional cytogenetic
studies. FISH does not replace cytogenetics.
Imaging Studies
-Chest radiographs
-Multiple gated acquisition (MUGA) scanning is needed once the diagnosis is of
acute myelogenous leukemia (AML) is confirmed, because many chemotherapeutic
agents used in treatment are cardiotoxic.
Other Tests
Electrocardiography should be performed before treatment of acute myelogenous
leukemia (AML).

Procedures

Bone marrow aspiration and biopsy are the definitive

diagnostic tests for acute myelogenous leukemia (AML).

Aspiration slides are stained for morphology with either Wright or Giemsa stain.
To determine the FAB type of the leukemia, slides are also stained with
myeloperoxidase (or Sudan black),
terminal deoxynucleotidyl transferase (TdT) (unless performed
by another method [eg, flow cytometry]),
double esterase (see Histologic Findings).

Bone marrow samples should also be sent for cytogenetics testing and
flow cytometry.
Patients with APL should have their marrow evaluated for the PML/RARa genetic
rearrangement.
When possible, the bone marrow should be evaluated for FLT3 and NPM1 mutations.
FAB classification of acute myelogenous leukemia (AML) is as
follows:

M0 - Undifferentiated leukemia
M1 - Myeloblastic without differentiation
M2 - Myeloblastic with differentiation
M3 - Promyelocytic
M4 - Myelomonocytic
M4eo - Myelomonocytic with eosinophilia
M5 - Monoblastic leukemia
M5a - Monoblastic without differentiation
M5b - Monocytic with differentiation
M6 - Erythroleukemia
M7 - Megakaryoblastic leukemia
The WHO classification is as follows :

Acute myelogenous leukemia (AML) with recurrent genetic abnormalities

AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)
(q22), (CBFB/MYH11)
APL with t(15;17)(q22;q12), (PML/RARa) and variants
AML with 11q23 (MLL) abnormalities
AML with multilineage dysplasia
Following MDS or MDS/myeloproliferative disease (MPD)
Without antecedent MDS or MDS/myeloproliferative disease (MPD) but with dysplasia
in at least 50% of cells in 2 or more lineages
AML and MDS, therapy related
Alkylating agent or radiation-related type
Topoisomerase II inhibitor type
Others
AML, not otherwise classified
AML, minimally differentiated
AML, without maturation
AML, with maturation
Acute myelomonocytic leukemia
Acute monoblastic or monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis and myelofibrosis
Myeloid sarcoma
TREATMENT
(excluding acute promyelocytic leukemia)
Induction therapy: 3+7

=3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or

anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (ara-
C) as a 24-hour infusion daily for 7 days.
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% of patients enter remission following a second course of therapy.

Consolidation therapy
-in younger patients:
High-dose ara-C therapy
3 g/m2 in a 3-hour infusion every 12 hours on days 1, 3,
and 5.

The probability of remaining in continuous complete remission after 4 years in patients

aged 60 years or younger was 44%.

In order to define the best postremission therapy for young patients, several large,
randomized studies have compared allogeneic bone marrow transplantation (BMT),
autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these
studies are conflicting.

Some studies suggest an advantage to BMT.

Several other studies have failed to show any advantage to BMT.
In view of these conflicting results, the following recommendations can be made:

Patients with good-risk acute myelogenous leukemia

(AML) (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis
following consolidation with high-dose ara-C and should be offered such therapy. This
is given as ara-C at 3 g/m2 twice a day on days 1, 3, and
5 of each cycle, repeated monthly (after recovery from
the previous cycle) for 4 consolidation cycles.
Transplantation should be reserved for patients who
have a relapse.

Patients with high-risk cytogenetics findings are rarely cured

with chemotherapy and should be offered transplantation in first remission. However,
these patients also are at high risk for a relapse following transplantation.
- intermediate-risk cytogenetics findings :controversial.

Consolidation therapy in older patients

No standard consolidation therapy exists for patients older than 60 years. Options include
a clinical trial, high-dose ara-C in select patients, or repeat courses of standard-dose
anthracycline and ara-C (2 and 5; ie, 2 d of anthracycline and 5 d of ara-C). Select
patients can be considered for autologous stem cell transplantation or nonmyeloablative
allogeneic transplantation.
Nonmyeloablative allogeneic transplantation
Treatment of APL
APL is a special subtype of acute myelogenous leukemia (AML). APL differs from other
subtypes of AML in that patients are, on average, younger (median age 40 y) and most
often present with pancytopenia rather than with elevated WBC counts. In fact, WBC
counts higher than 5000 cells/µL at presentation are associated with a poor prognosis.

APL is the subtype of acute myelogenous leukemia (AML) that is most commonly
associated with coagulopathy due to DIC and fibrinolysis. Therefore, aggressive
supportive care is an important component of the treatment of APL. Platelets should be
transfused to maintain a platelet count of at least 30,000/µL (preferably 50,000/µL).
Administer cryoprecipitate to patients whose fibrinogen level is less than 100 g/Dl.

The bone marrow demonstrates the presence of more than 30% blasts resembling
promyelocytes. These cells contain large dense cytoplasmic granules along with varying
numbers of Auer rods.

Although the initial diagnosis of APL is based on morphology, the diagnosis is confirmed
based on cytogenetic and molecular studies. Do not delay treatment pending the results of
confirmatory tests. In more than 95% of cases of APL, cytogenetic testing reveals
t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with
either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid
(ATRA) and chemotherapy.

A small percentage of patients have other cytogenetic abnormalities, including t(11;17)

(q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17)
(q23;q11) are resistant to all-trans-retinoic acid (ATRA). Older studies using standard
chemotherapy regimens without ATRA showed that approximately 70% of patients
achieved complete response and 30% were disease free at 5 years. Induction failures were
due to deaths resulting from hemorrhage caused by DIC, with few actual resistant
cases.26,27,28
Currently, the most standard approach is the
combination of ATRA and anthracycline-based
chemotherapy.

Supportive care :

Replacement of blood products

Antibiotics
Allopurinol
Use of growth factors

Surgical Care
Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.

Diet
Patients with acute myelogenous leukemia (AML) should be on a neutropenic diet (ie, no
fresh fruits or vegetables). All foods should be cooked. Meats should be cooked
completely (ie, well done).