Acute myeloid leukaemia

The leukaemias are a group of disorders characterized by the accumulation of malignant white
cells in the bone marrow and blood.
These abnormal cells cause symptoms because of:
(i) bone marrow failure (e.g. anaemia, neutropenia, thrombocytopenia); and
(ii) infiltration of organs (e.g. liver, spleen, lymph nodes, meninges, brain, skin or testes )

LEUKEMIAS

MYLOID LYMPHOID

ACUTE CRONIC CRONIC

ACUTE

Acute leukaemias
are usually aggressive diseases in which malignant transformation occurs in the haemopoietic stem cell
or early progenitors
steps resulting in (i) an increased rate of proliferation, (ii) reduced apoptosis and (iii) a block in cellular
differentiation
Together these events cause accumulation in the bone marrow of early haemopoietic cells known as
blast cells. The dominant clinical feature of acute leukaemia is usually bone marrow failure caused by
accumulation of blast cells, although organ infiltration also occurs. I

Diagnosis of acute leukaemia

Acute leukaemia is normally defined as the presence of over 20% of blast cells in the bone marrow at
clinical presentation. However, it can be diagnosed with less than 20% blasts if specific leukaemia‐
associated cytogenetic or molecular genetic abnormalities are present
The lineage of the blast cells is defined by microscopic examination (morphology)
immunophenotypic (flow cytometry), cytogenic
This will define whether the blasts are of myeloid or lymphoid lineage and molecular analysis (This will
define whether the blasts are of myeloid or lymphoid lineage and also localize the stage of cellular
differentiation .
The typical ‘myeloid
immunophenotype’ is CD13, CD33+
and TdT
Special antibodies are helpful in the
diagnosis of the rare
undifferentiated, erythroid or
megakaryoblastic subtypes
Cytogenetic and molecular analysis is
essential and is usually performed on
marrow cells, although blood may be
used if the blast cell count is
particularly high. Cytochemistry can
be useful in determining the blast
cell lineage

Acute myeloid leukaemia

Pathogenesis
The AML genome contains an average of about 10 mutations within protein‐coding genes Many AML
‘driver mutations’ have been identified, with the most common being within FLT3, NPM1 and DNMT3A
The mutations usually occur on only one of the two alleles for the gene and may be ‘loss of function’ or
‘gain of function’.
The average AML at presentation contains less than one gene‐ fusion event, which usually arise from
translocations, with the most common being PML‐RARA, CBFB‐MYH11, RUNX1- RUNX1T1

Incidence
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults

Classification
AML is classified according to the World Health Organization (2008) scheme Six main groups of AML are
recognized

 A ML with recurrent genetic abnormalities

 AML with myelodysplasia‐related changes.
 Therapy‐related myeloid neoplasms(t‐AML)
 AML, not otherwise specified.
 Myeloid sarcoma
 Myeloid proliferations related to Down’s syndrome.
 Clinical features
The clinical features of AML are dominated by the pattern of bone marrow failure caused by the
accumulation of malignant cells within marrow
Infections are frequent, and anaemia and thrombocytopenia are often profound
Gum hypertrophy and infiltration
orbital infection
Skin infection

Investigations
Assessment of medical history, examination and

 performance status
 Full blood count and differential
 Bone marrow aspirate and trephine biopsy
 Immunophenotyping of bone marrow (and/or blood if blast cells present)
 Cytogenetic analysis by karyotype
 Mutation analysis
 Cytochemical analysis (performed in some countries instead of immunophenotyping)
 Biochemistry (liver, renal, uric acid, calcium, LDH)
 Coagulation
 Pregnancy test
 Information on oocyte or sperm storage
 Assessment of eligibility for stem cell transplantation
 Hepatitis B, C and HIV test
 CXR with ECG and ECHO in older patients

Treatment
Management is both supportive and specific.

General supportive therapy

The aim of treatment in acute leukaemia is to induce

complete remission (less than 5% blasts in the bone
marrow, normal blood counts and clinical status) and
then to consolidate this with intensive therapy,
hopefully eliminating the disease Allogeneic stem cell
transplantation is considered in poor prognosis cases
or for patients who have relapsed.

Specific therapy of AML

Acute leukaemia: principles of therapy for AML or ALL
(acute lymphoblastic leukaemia); SCT, stem cell
transplantation; TBI, total body irradiation.
The decision for SCT in remission is based on prognostic factors as well as tests for minimal residual
disease.

Prognosis and treatment stratification

The outcome for an individual patient with AML will depend on a number of factors including age and
white cell count at presentation Complete remission is defined as less than 5% blasts without Auer rods,
neutrophil count greater than 1.0x109/L, platelets greater than 100 x109 /L, independence of red cell
transfusions and no extramedullary disease
The prognosis for patients with AML has been improving steadily, particularly for those under 60 years
of age, and approximately one‐third of this group can expect to achieve long‐term cure. The outcome
for elderly people remains disappointing.
Allogeneic stem cell transplantation is useful in treating some subsets of patients and may also be
curative for patients with relapsed disease.
 Chronic myeloid leukaemia
The chronic leukaemias are distinguished from acute leukaemias by their slower progression. Chronic
leukaemias can be broadly subdivided into myeloid and lymphoid groups

Chronic myeloid
leukaemia
Chronic myeloid leukaemia BCR‐
ABL1+ (CML) is a clonal disorder of
a pluripotent stem cell.
The diagnosis of CML is rarely
difficult and is assisted by the
characteristic presence of the
Philadelphia (Ph) chromosome.
This results from the t(9;22)
(q34;q11) translocation between
chromosomes 9 and 22, as a result
of which part of the oncogene ABL1
is moved to the BCR gene on
chromosome 22 and part of
chromosome 22 moves to
chromosome 9.

The abnormal chromosome 22 is

the Ph chromosome. In the Ph
translocation 5′ exons of BCR are fused to
the 3′ exons of ABL1
The resulting chimeric BCR‐ABL1 gene
codes for a fusion protein of size 210kDa
(p210). This has tyrosine kinase activity in
excess of the normal 145‐kDa ABL1
product. The Ph translocation is also seen
in a minority of cases of acute
lymphoblastic leukaemia (ALL) and in some
of these the breakpoint in BCR occurs in
the same region as in CML. However, in
other cases the breakpoint in BCR is further
upstream, in the intron between the first
and second exons, leaving only the first
BCR exon intact
This chimeric BCR‐ ABL1 gene is expressed
as a p190 protein which, like p210, has
enhanced tyrosine kinase activity
In most patients the Ph chromosome is seen by karyotypic examination of tumour cells As the Ph
chromosome is an acquired abnormality of haemopoietic stem cells it is found in cells of both the
myeloid (granulocytic, erythroid and megakaryocytic) and lymphoid (B and T cell) lineages. The main
cause of death in CML is transformation to a blast phase, which may be preceded by an accelerated
phase
BCR-ABL1‐negative chronic myeloid leukaemia is classified with the myelodysplastic/myeloproliferative
syndromes

Clinical features
This disease occurs in either sex (male: female ratio of 1.4 : 1) most frequently between the ages of 40
and 60 years the following features may be seen:

1) Symptoms related to hypermetabolism (e.g. weight loss,lassitude, anorexia or night sweats).

2) Splenomegaly is nearly always present and may be massive. In some patients splenic
enlargement is associated with considerable discomfort, pain or indigestion.
3) Features of anaemia may include pallor, dyspnoea and tachycardia.
4) Bruising, epistaxis, menorrhagia or haemorrhage from other sites because of abnormal
platelet function.
5) Gout or renal impairment caused by hyperuricaemia from excessive purine breakdown may
be a problem.
6) Rare symptoms include visual disturbances and priapism

Laboratory findings
 Leucocytosis is the main feature and may reach levels greater than 200× 109. A complete
spectrum of myeloid cells is seen in the peripheral blood. The levels of neutrophils and
myelocytes exceed those of blast cells and promyelocytes.
 Increased circulating basophils are a characteristic feature.
 Normochromic normocytic anaemia is usual.
 Platelet count may be increased (most frequently), normal or decreased.
 Bone marrow is hypercellular with granulopoietic predominance.
 Presence of the BCR‐ABL1 gene fusion by RT‐PCR analysis and in 98% of cases Ph chromosome
on cytogenetic analysis.
 Serum uric acid is usually raised.

Prognostic scores (stages)

The most frequently used is the Sokal score, which takes account of age, blast cell percentage, spleen
size and platelet count which takes account of age, blast cell percentage, spleen size and platelet count.
However the rate of response to a tyrosine kinase inhibitor is now a more useful measure.
 Treatment
Treatment of chronic phase

 Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKI) are the mainstay of the treatment of CML and several different
drugs are now available
Monitoring of response to tyrosine kinase inhibitors (TKI)
 BCR‐ABL1 mutation screening
 Response to TKI therapy

Additional forms of treatment for CML

 Chemotherapy
 α‐Interferon
 α‐Interferon

Accelerated phase disease and blastic transformation

Acute transformation (greater than 20% blasts in blood or marrow) may occur rapidly over days or
weeks
More commonly there is an accelerated phase with anaemia, thrombocytopenia (platelets less than
100×109 /L), increase in blood basophils to greater than 20% or marrow blast cells 10–19% with blast
cells in the blood. The spleen may be enlarged despite control of the blood count and the marrow may
be fibrotic. New clonal chromosomal or molecular abnormalities may appear

Chronic neutrophilic leukaemia And Chronic eosinophilic leukaemia