ACUTE MYELOBLASTIC

LEUKAEMIA
BY
DR HALIMA TALBA
CONSULTANT HAEMATOLOGIST
DEPARTMENT OF HAEMATOLOGY AND BTS
 OUTLINE
• INTRODUCTION
• EPIDEMIOLOGY
• RISK FACTORS
• CLASSIFICATION
• PATHOGENESIS
• CLINICAL FEATURES
• INVESTIGATION
• DIAGNOSIS
• TREATMENT
 INTRODUCTION
• 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
1. Bone marrow failure (Anaemia, Neutropenia,
Thrombocytopaenia)
2. Infiltration of organs (Spleen, Lymph nodes,
Meninges, Brain, Skin or Testes)
• Acute leukaemias are usually aggressive
disease in which malignant transformation
occurs in the haemopoietic stem cell or early
progenitors. Genetic damage is believed to
involve several key biochemical steps resulting
in (1) An increased rate of proliferation.
(2) Reduced apoptosis
(3) Block in cellular differentiation
Together these events cause accumulation in
the bone marrow of early haemopoeitic 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 infilteration also
occurs. If untreated, acute leukaemias are
usually rapidly fatal.
 EPIDEMIOLOGY
 AML is the most common form of acute
leukaemia in adults and becomes increasingly
common with age.
 The median age onset is 65 years.
 Acute myeloid leukaemia (AML) has an incidence
of 2–3 per 100 000 per annum in children, rising
to 15 per 100 000 in older adults.
 The fact that most cases occur in older patients
has important implications for treatment
strategies
 RISK FACTORS
• Old Age
• Previous exposure to radiation: Radiation
especially to the marrow is leukeamogenic.
Radiation treatment for a previous cancer, low
level radiation such as from CT-Scans or X-rays
though controversial.
• Drugs: Previous chemotherapy drugs used to
treat previous cancer.
• Alkylating agents such as chlorambucil or
melphalan especially if combined with
radiotherapy.
• Topoisomerase II inhibitors like etoposide and
tenoposide.
• Environmental factors:
• The only proven lifestyle related risk factor for
AML is smoking.
• Chemicals: Benzene is a solvent used in rubber
industry, oil refineries, chemical plants, shoe
manufacturing and gasoline related industries.
• Formaldehyde: not well established
• Certain blood disorders (Malignancy): Chronic
myeloid leukaemia, Polycythaemia vera,
Essential thrombocytosis, Primary and
Secondary Myelofibrosis and Myelodysplastic
Syndrome.
• Chromosome problems at birth:
• Down syndrome (Trisomy 21)
• Trisomy 8
• Genetic conditions
• Ataxia telangiectasia
• Blooms syndrome
• Neurofibromatosis
• Klinefelters syndrome
• Fanconis Anaemia
• Wiskott Aldrich Syndrome
• Schwachman diamond syndrome
• Diamond blackfan Anaemia
• Li-Fraumeni syndrome
• Severe Congenital Neutropeania (kotsmann
syndrome)
 CLASSIFICATION
• The French-American-British (FAB)
classification.
• WHO classification
• The FAB subtypes M1 and M2 with Auer rods
are standard risk diseases.
• M3 and M4Eo are also standard risk diseases.
• All others are high risk diseases with poor
prognosis.
 FAB CLASSIFICATION
• M0 minimal myeloid maturation, no Auer rods,
<3% blast.
• M1 no maturation and poorly differentiated, few
granules and Auer rod
• M2 AML with myeloid maturation, well
differentiated with granular blast and Auer rods
• M3 APL, hypergranular promyelocytes, Auer rods
and high risk of DIC.
• M4 AMML, similar to M2 but marrow monocytes
>20% and increased marrow eosinophils.
 Cont...
• M5 Acute monocytic leukaemia, over 80% of
marrow non erythroid cells are monocytic +
extramedullary tissue infiltration.
• M6 Erythroleukaemia, marrow erythrocytes
>50% of all nucleated cells and myeloblast >20%
of non erythroid cells.
• M7 Acute megakaryoblastic leukaemia,
myeloblast >20% of non-erythroid cells
•The World Health Organization 2016 updated guidelines
distinguishes six groups of AML: based on
•Genetic abnormalities (molecular investigations)
•cytogenetic abnormalities
•(1) AML with recurrent genetic abnormalities
•(2) AML with myelodysplasia-related changes,
•(3) Therapy-related myeloid neoplasms,
•(4) AML Not Otherwise Specified,
•(5) Myeloid sarcoma, and
•(6) Myeloid proliferations related to Down syndrome.
 PATHOPHYSIOLOGY
• Acute myeloid leukaemia is a malignant clonal
disorder of immature cells in the haemopoietic
hierarchical system.
• Leukaemic transformation is assumed to occur
in many cases at, or near, the level of the
haemopoietic stem cell before it has embarked
on any lineage commitment.
• Some cases may originate at a slightly later
stage in cells that are committed to lineage
differentiation.
 Cont...
• These cells have abnormal function
characterized by a failure to progress through
the expected differentiation programme and/
or to die by the process of apoptosis.
• Associated with this may be the retention of
the stem cell characteristic of self-renewal.
• Adenopathy or organomegaly can occur but
are not usual features.
 Cont...
• Non-random chromosome abnormalities are found
in the majority of cases.
• The most common molecular mutation associated
with AML has been found in the FLT receptor.
• The receptor is expressed in haemopoietic cells
restricted to the CD34-positive fraction and a CD34-
negative subfraction of dendritic cell precursors.
• Normal FLT-3 receptor is expressed on AML blasts
in most cases and can be over expressed or
asynchronously expressed in that it can be expressed
not strictly in association with CD34 expression.
 Cont...
• Additional point mutations have been found
on the activation loop of the interrupted
kinase domain, usually at aspartate-835.
• The consequence of these mutations are
activation of the receptor by phosphorylation,
which promotes proliferation and resistance to
apoptosis.
• Mutations are associated with high white cell
counts and blast percentage at diagnosis.
 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.
• Features of infection
• Features of anaemia
• Bleeding tendency and DIC
• Tissue infiltration (Gum hypertrophy)
GUM HYPERTROPHY
 DIAGNOSIS
– Baseline investigation: FBC, Clotting profile, EUC,
LFT, Viral markers
– Blood film: Rbc- Normochromic normocytic
anaemia
– WBC- Leucocytosis with maturation arrest and
blast of >20%.
• Platelets- Thrombocytopaenia
• Bone marrow: Hypercellular and contains
predominantly myeloblast blast.
• Immunophenotypic and cytogenetic analysis
 Cont...
 CYTOCHEMICAL STAINS: myeloperoxidase, Sudan
Black B and Non-specific esterases.
 PHENOTYPES:
-Specific myeloid Ags CD13, CD33, CD 117.
-Monocytic markers CD14 and CD64.
-Erythroblast markers Glycophorin A.
-Megakaryoblast marker CD41
 CLONAL CYTOGENETICS: t(8;21), t(15,17), t(6,9)
 TREATMENT
 Management is both supportive and specific
 Given the age distribution of patients who will
present with the disease, it must first be
decided what the goals of treatment are in an
individual patient.
 In young people, intensive approach is
instituted.
 A substantial majority of older patients are not
considered fit for the usual intensive approach
 Cont...
 The initial clinical priority is to apply chemotherapy
to improve marrow function by inducing complete
remission (CR).
 Complete Remission: < 5% blast cells in a cellular
marrow durable for at least 28 days with a
peripheral neutrophil count of 1.5 × 10⁹/L and
platelet count of > 100 × 10⁹/L, and absence of
extramedullary disease.
 Complete Remission is compatible with a normal
marrow which appears normal morphologically and
functionally.
 Cont...
 Clinical experience has demonstrated that
further intensive post-remission treatment is
required to ‘consolidate’ CR.
 This is delivered at the same intensity as
induction, to achieve further cytoreduction.
 It is possible to achieve disease levels that are
beyond the level of molecular detection.
 It is not clear how many intensive consolidation
courses are required
 SUPPORTIVE CARE
 Nursing expertise is an essential component. It seems
probable that improvements in remission rates in
recent years can largely be attributed to better
supportive care and nursing skills which have enabled
more intensive treatment to be given safely.
 It is unusual for induction chemotherapy not to clear
most of the leukaemic blasts.
 Careful monitoring of biochemical parameters of renal
function, hepatic function and coagulation is required.
 Central venous access is now considered essential,
together with high-quality and readily available blood
product support.
 Cont...
 A priority is the prevention and management of
infection.
 Since hospital-acquired infections are becoming
an increasing problem, it can be safer for the
patient to be at home provided that close
monitoring can be undertaken.
 In spite of prophylactic measures, most patients
will become febrile during neutropenia. This must
be considered as an indication of a serious, and
potentially fatal, infection.
 Remission Induction
 The backbone of treatment for 30 years has been
the combination of daunorubicin and cytosine
arabinoside (Ara-C).
 Usually daunorubicin is given for 3 days in a dose of
45–50 mg/m².
 Ara-C is given for 7–10 days as a continuous infusion
or by bolus doses of 100–200 mg/m²/day.
 The beneficial effect of the addition of a third drug
to the induction combination has some evidence to
support it etoposide or thioguanine
 Consolidation
 Having achieved remission, the priority is to prevent
relapse.
 Three options are available for younger patients
once remission has been achieved:
1. further chemotherapy at induction level of
intensity.
2. chemotherapy with autologous stem cell
transplantation.
3. Allogeneic stem cell transplant with or without
prior chemotherapy
 STEM CELL TRANSPLANTATION
ALLOGENIC SCT:
- Allogeneic transplantation from an HLA-compatible sibling
donor.
- The relapse risk will be reduced from 45% to about 20%.
- The overall expectation of cure for recipients of allo-BMT
is around 60%.
- The risk of transplant complications, graft-versus-host
disease (GvHD) and infections is high.
- Some factors favour a favourable outcome: viz a male
donor, a cytomegalovirus (CMV)-negative donor when the
host is CMV negative and a higher cell count in the graft
 AUTOLOGOUS SCT
 For younger patients who lack donors, harvesting stem
cells from the bone marrow or peripheral blood during
remission.
 This approach has also been shown to be a more
effective way of preserving remission compared with
chemotherapy.
 The relapse risk is higher (around 35–40%).
 Patients up to their mid-50s can safely undergo this
procedure, but the results of autologous transplant in
older patients (over 60 years) is not encouraging.
 One of the problems with the use of autologous bone
marrow has been delayed peripheral blood count