ACUTE MYELOID

LEUKAEMIA
Mrs. NEERAJA RAJIV
BPT MPT MIAP
ACUTE MYELOID LEUKAEMIA

Definition
Acute myeloid leukaemia (AML) is a heterogeneous
disease characterised by infiltration of malignant
myeloid cells into the blood, bone marrow and other
tissues.
AML is mainly a disease of adults (median age 50
years), while children and older individuals may also
develop it.
ETIOLOGY
AML develops due to inhibition of maturation of
myeloid stem cells due to mutations.
These mutations may be induced by several etiologic
factors—
heredity
radiation
chemical carcinogens (tobacco smoking,
rubber, plastic, paint, insecticides etc)
long-term use of anti-cancer drugs
PATHOPHYSIOLOGY
In normal haematopoiesis, myeloblast is an immature
precursor of myeloid WBC: ie normally myeloblast
matures into a mature WBC.
In AML,a single myeloblast genetic changes which
freeze the cell in its immature form and prevent
differentiation.
The defect induced by mutations causes accumulation
of precursor myeloid cells of the stage at which the
myeloid maturation and differentiation is blocked.
A few important examples of chromosomal mutations
in AML are translocations {t(8;21)(q22q22) and t(15;17)
(q22;q12)} and inversions { inv(16)(p13;q22)}.
When such a differentiation arrest is combined with
other mutations which disrupt genes controlling
proliferation, results in uncontrolled growth of an
immature clone of cell and leads to clinical entity of
AML.
CLASSIFICATION
Currently, two main classification schemes for AML are
followed:
FAB CLASSIFICATION.
According to revised FAB clasification system, a
leukaemia is acute if the bone marrow consists of
more than 30% blasts.
Based on morphology and cytochemistry, FAB
classification divides AML into 8 subtypes (M0 to M7)
WHO CLASSIFICATION (2002).
WHO classification for AML differs from revised FAB
classification in the following 2 ways:
1.It places limited reliance on cytochemistry for making the
diagnosis of subtype of AML but instead takes into
consideration clinical, cytogenetic and molecular
abnormalities in different types. These features can be
studied by multiparametric flow cytometry.
2. WHO classification for AML has revised and lowered the
cut off percentage of marrow blasts to 20% from 30% in
the FAB classification for making the diagnosis of AML.
ACUTE MYELOID LEUKAEMIA (AML)
1. AML with recurrent cytogenetic abnormalities
i) AML with t(8;21)(q22;q22)
ii) AML with abnormal bone marrow eosinophils
{inv(16) (p13q22)}
iii) Acute promyelocytic leukaemia {t(15;17)(q22;q12)}
iv) AML with 11q23 abnormalities (MLL)

2. AML with multilineage dysplasia

i) With prior MDS
ii) Without prior MDS
 3. AML and MDS, therapy-related
i) Alkylating agent-related
ii) Topoisomerase type II inhibitor-related
iii) Other types

 4. AML, not otherwise categorized

i) AML, minimally differentiated
ii) AML without maturation
iii) AML with maturation
iv) Acute myelomonocytic leukaemia (AMML)
v) Acute monoblastic and monocytic leukaemia
vi) Acute erythroid leukaemia
vii) Acute megakaryocytic leukaemia
viii) Acute basophilic leukaemia
ix) Acute panmyelosis with myelofibrosis
CLINICAL FEATURES

Clinical manifestations of AML are divided into 2

groups:
 Due to bone marrow failure,
 Due to organ infiltration
I. DUE TO BONE MARROW FAILURE.
1. Anaemia producing pallor, lethargy, dyspnoea.
2. Bleeding manifestations due to thrombocytopenia
causing spontaneous bruises, petechiae, bleeding from
gums and other bleeding tendencies.
3. Infections are quite common and include those of
mouth, throat, skin, respiratory, perianal and other
sites.
4. Fever is generally attributed to infections in acute
leukaemia but sometimes no obvious source of infection
can be found and may occur in the absence of infection.
II. DUE TO ORGAN INFILTRATION.
The clinical manifestations of AML are more often due to
replacement of the marrow and other tissues by leukaemic cells.
These features are as under:
 1. Pain and tenderness of bones (e.g. sternal tenderness) are due
to bone infarcts or subperiosteal infiltrates by leukaemic cells.
 2. Lymphadenopathy and enlargement of the tonsils may occur.
 3. Splenomegaly of moderate grade may occur. Splenic infarction,
subcapsular haemorrhages, and rarely, splenic rupture may occur.
 4. Hepatomegaly is frequently present due to leukaemic
infiltration but the infiltrates usually do not interfere with the
function of the liver.
 5. Leukaemic infiltration of the kidney may be present and
ordinarily does not interfere with its function unless secondary
complications such as haemorrhage or blockage of ureter
supervene.
6. Gum hypertrophy due to leukaemic infiltration of the gingivae is a
frequent finding in myelomonocytic (M4) and monocytic (M5)
leukaemias.

7. Chloroma or granulocytic sarcoma is a localised tumourforming mass
occurring in the skin or orbit due to local infiltration of the tissues by
leukaemic cells. The tumour is greenish in appearance due to the
presence of myeloperoxidase.

8. Meningeal involvement manifested by raised intracranial pressure,

headache, nausea and vomiting, blurring of vision and diplopia are seen
more frequently in ALL during haematologic remission. Sudden death
from massive intracranial haemorrhage as a result of leucostasis may
occur.

9. Other organ infiltrations include testicular swelling and mediastinal

LABORATORY FINDINGS
The diagnosis of AML is made by a combination of routine
blood picture and bone marrow examination, coupled with
cytochemical stains and other special laboratory investigations.
I. BLOOD PICTURE.

1. Anaemia. Anaemia is almost always present in AML. It is

generally severe, progressive and normochromic. A moderate
reticulocytosis up to 5% and a few nucleated red cells may be
present.

2. Thrombocytopenia. The platelet count is usually

moderately to severely reduced (below 50,000/μl) but
occasionally it may be normal. Most serious spontaneous
haemorrhagic episodes develop in patients with fewer than
20,000/μl platelets.
3. White blood cells.
The total WBC count ranges from subnormal-to-
markedly elevated values.
In 25% of patients, the total WBC count at
presentation is reduced to 1,000-4,000 /μl.
II. BONE MARROW EXAMINATION.
1. Cellularity. Typically, the marrow is hypercellular but
sometimes a ‘blood tap’ or ‘dry tap’ occurs. A dry tap in AML may
be due to pancytopenia, but sometimes evenwhen the marrow is
so much filled with leukaemic cells that they cannot be aspirated
because the cells are adhesive and enmeshed in reticulin fibres. In
such cases, trephine biopsy should be done.

2. Leukaemic cells. The bone marrow is generally tightly packed

with leukaemic blast cells. The essential criteria for diagnosis of
AML, as per FAB classification, was the presence of at least 30%
blasts in the bone marrow. However, as per WHO classification,
these criteria have been revised and lowered to 20% blasts in the
marrow for labelling and treating a case as AML.
3. Erythropoiesis. Erythropoietic cells are reduced.
Dyserythropoiesis, megaloblastic features and ring sideroblasts
are commonly present.

4. Megakaryocytes. They are usually reduced or absent.


5. Cytogenetics. Chromosomal analysis of dividing leukaemic
cells in the marrow shows karyotypic abnormalities in 75% of
cases which may have a relationship to prognosis. WHO
classification emphasises on the categorisation of AML on the
basis of cytogenetic abnormalities.

6. Immunophenotyping. AML cells express CD13 and CD33

antigens. M7 shows CD41 and CD42 positivity.
III. CYTOCHEMISTRY.
Some of the commonly employed cytochemical stains, as an aid to
classify the type of AML are as under
 1. Myeloperoxidase: Positive in immature myeloid cells containing
granules and Auer rods but negative in M0 myeloblasts.
 2. Sudan Black: Positive in immature cells in AML.
 3. Periodic acid-Schiff (PAS): Positive in immature lymphoid cells
and in erythroleukaemia (M6).
 4. Non-specific esterase (NSE): Positive in monocytic series (M4
and M5).
 5. Acid phosphatase: Focal positivity in leukaemic blasts in ALL
and diffuse reaction in monocytic cells (M4 and M5).
IV. BIOCHEMICAL INVESTIGATIONS.
1. Serum muramidase. Serum levels of lysozyme (i.e.
muramidase) are elevated in myelomonocytic (M4)
and monocytic (M5) leukaemias.
2. Serum uric acid. Because of rapidly growing
number of leukaemic cells, serum uric acid level is
frequently increased. The levels are further raised after
treatment with cytotoxic drugs because of increased
cell breakdown.
TREATMENT AND COMPLICATIONS

The management of acute leukaemia involves the

following aspects:
TREATMENT OF ANAEMIA AND HAEMORRHAGE.
Anaemia and haemorrhage are managed by fresh
blood transfusions and platelet concentrates.
Patients with severe thrombocytopenia (platelet count
below 20,000/μl) require regular platelet transfusions
since haemorrhage is an important cause of death in
these cases.
TREATMENT AND PROPHYLAXIS OF INFECTION.
 Neutropenia due to bone marrow replacement by leukaemic blasts
and as a result of intensive cytotoxic therapy renders these patients
highly susceptible to infection.
 The infections are predominantly bacterial but viral, fungal, and
protozoal infections also occur.
 For prophylaxis against infection in such cases, the patient should be
isolated and preferably placed in laminar airflow rooms.
 Efforts are made to reduce the gut and other commensal flora which
are the usual sourceof infection. This is achieved by bowel
sterilisation and by topical antiseptics.
 If these fail to achieve the desired results, systemic antibiotics and
leucocyte concentrates are considered for therapy.
III.CYTOTOXIC DRUG THERAPY.
The aims of cytotoxic therapy are firstly to induce
remission, secondly to continue therapy to reduce the
hidden leukaemic cell population by repeated courses
of therapy.
Most commonly, cyclic combinations of 2, 3 and 4
drugs are given with treatment free intervals to allow
the bone marrow to recover.
The most effective treatment of AML is a combination
of 3 drugs: cytosine arabinoside, anthracyclines
(daunorubicin, adriamycin) and 6-thioguanine.
Another addition is amsacrine (m-AMSA)
administered with cytosine arabinoside, with or
without 6-thioguanine.
Following remission-induction therapy, various drug
combinations are given intermittently for
maintenance.
However, promyelocytic leukaemia (M3) is treated
with tretinoin orally that reduces the leukaemic cells
bearing t(15;17)(q22;q21) but devlopment of DIC due to
liberation of granules of dying cells is a problem.
IV.BONE MARROW TRANSPLANTATION.
Bone marrow (or stem cell) transplantation from
suitable allogenic or autologous donor (HLA and
mixed lymphocytes culturematched) is increasingly
being used for treating young adults with AML in first
remission.
The basic principle of marrow transplantation is to
reconstitute the patient’s haematopoietic system after
total body irradiation and intensive chemotherapy
have been given so as to kill the remaining leukaemic
cells.
Bone marrow transplantation has resulted in cure in
about half the cases.
Remission rate with AML is lower (50-70%) than in
ALL, often takes longer to achieve remission, and
disease-free intervals are shorter.
AML is most malignant of all leukaemias; median
survival with treatment is 12-18 months