Week 2 - Acute Myeloid Leukaemia

Question 1

Definition of Acute Myeloid Leukaemia (AML)

Answer 1

Accumulation of clonal immature cells from the myeloid lineage in the bone marrow that interferes with normal production
≥ 20% blasts

Question 2

AML Risk Factors

Answer 2

Smoking
Chemicals
Radiation
Viruses
Congenital syndromes (some - increase risk)
Certain blood disorders

Question 3

AML Morphology

Answer 3

Peripheral blood film
- mostly diagnostic, blasts & accompanying changes provide good clues
Bone marrow aspirate
- detailed morphology of cells, good for quantitating
Bone marrow trephine
- marrow cellularity & cellular pattern of involvement

Question 4

AML Blood Film

Answer 4

Leukoerythroblastic film
Dimorphic RBC’s
Dysplastic neutrophils
Pelger Huet
Monocytosis (+ abn forms)
Platelet anisocytosis, large forms
Nucleated RBC’s

Question 5

Myeloid Blasts Characteristics

Answer 5

Size - medium to large
N/C ratio - high (except monoblasts)
Nucleus - round
Chromatin - open
Nucleoli - obvious >1
Cytoplasm - pale blue/grey, granules, vacuolation (M4/5)
Auer rods - present

Question 6

AML Coagulation Studies

Answer 6

Disseminated intravascular coagulation (DIC) common
Acute promyelocytic leukemia (APML) results in:
- increased PT
- decreased fibrinogen
- positive fibrin split products

Question 7

Role of Immunophenotyping in Acute Leukaemia (Flow Cytometry)

Answer 7

Determine cell of origin - myeloid vs lymphoid
Identify blast population e.g. subgroups of lymphoma
Determine clonality
Quantification

Question 8

Myeloid Antigens Present in AML

Answer 8

CD11b, CD13, CD33, CD34, CD45, CD117, HLA DR (markers of immaturity)

Question 9

Role of Molecular Haematology in AML

Answer 9

Detect fusion transcripts generated by novel fusion genes & monitor
Monitors engraftment post bone marrow transplant
Detect SNP associated with AML
Amplify & detect small mutations FLT3, NPM & CEBPA
Sensitivity levels (good for MRD):
- conventional cytogenetics ~1:20
- FISH ~1:100 – 500
- immunophenotyping ~1:1000
- molecular (PCR) ~1:100,000

Question 10

Role of Clinical Cytogenetics in AML

Answer 10

Confirm diagnosis
Classify haematological malignancies and the subsets
Determine disease status
Stratify patients for treatment protocols & clinical trials
MRD
Predictive factors for prognosis

Question 11

Treatment Options

Answer 11

Curative
- chemotherapy
- transplant
Palliative
- supportive care

Question 12

Treatment Phases with Chemotherapy in AML

Answer 12

Induction
- induce remission
- ~70-80% of patients will achieve remission
Consolidation
- sustain a remission
- consolidation offered to relapse pts with or without transplant
Maintenance
- chemotherapy in lower doses to sustain remission
- usually only in APML

Question 13

AML Prognosis

Answer 13

AML a curable disease but overall survival for AML is ~ 30%

Within the good prognostic group, overall survival is 80%

Question 14

AML With Favourable Prognosis

Answer 14

Cytogenic Abnormalities

• t(15;17)(q24.1;q21) (PML:RARα)
• t(8;21)(q22;q22) (RUNX1:RUNXT1)
• inv(16)(p13q22)/t(16;16)(p13;q22) (MYH11:CBFβ)

Question 15

Acute Promyelocytic Leukaemia with PML::RARα

Answer 15

Causes DIC
Makes up 10% of AMLs
Med age of 30-40 yrs
Cytogenetic abnormality: t(15;17)(q24.1;q21)
- PML gene on 15q24.1 - regulatory factor
- RARα gene on 17q21 - ligand involved in the differential pathway of multiple tissues
- PML::RARα fusion - product has enhanced affinity to sites on the cell’s DNA, this blocks transcription and differentiation of granulocytes

Question 16

AML with t(8;21) RUNX1-RUNX1T1

Answer 16

Mostly associated with Acute myeloblastic leukaemia with maturation
Most common structural abnormality in AML (4-5%)
Occurs predominantly in younger patients
Cytogenetic abnormality: t(8;21)(q22;q22)
RUNX1 (AML1) gene on 21q22 - codes for a transcription factor
RUNX1T1 (ETO) gene on 8q22 - codes for CBFα (transcription factor)
RUNX1::RUNX1T1 fusion - product alters the transcriptional regulation of the normal RUNX1 target genes in haematopoiesis

Question 17

AML with inv(16) or t(16;16)

Answer 17

Acute MyeloMonocytic leukaemia
Detected in 5% of AMLs
Can occur in all age groups, predominates in younger group
inv (16)(p13q22) - majority cases associated with AMML Eo t(16;16)(p13;q22)
MYH11 gene at 16p13 - product converts chemical energy to mechanical energy
CBFβ gene at 16q22 - transcript factor regulates RUNX1 gene
CBFβ::MYH11 fusion - product binds to RUNX1 to inhibit it’s function in haematopoiesis

Question 18

AML with Intermediate Prognosis

Answer 18

Normal karyotype
Entities not classified as favourable or adverse
Trisomy 8
t(9;11)(p22;q23)
t(11;19)(q23;p13.1 or p13.3)

Question 19

AML with Adverse Prognosis

Answer 19

inv(3)(q21q26)/t(3;3)(q21;q26)
-5/ del(5q)
-7/del(7q)
abn(17p)
Complex ( ≥3 unrelated abnormalities)

Question 20

AML with inv(3)(q) or t(3;3)

Answer 20

Mostly seen in AML with multilineage dysplasia de novo or secondary AML following a MDS/MPD
Rare 1- 2%
Occurs mainly in elderly patients
Patients often present with severe pancytopaenia
inv (3)(q21;q26) or t(3;3)(q21;q26)
- RPN1 gene at 3q21
- MECOM (EVI1) gene part of MDS1/EVI1 complex at 3q26.2
- a PR-protein at MDS1/MECOM normally functions as a growth suppressor
- MECOM becomes upregulated by the PR-protein

Question 21

What is a Monosomal Karyotype

Answer 21

> 2 autosomal monosomies or 1 autosomal monosomy with at least one structural abnormality excluding rings or marker chromosomes
Very poor prognosis