Acute Leukaemia Flashcards
(91 cards)
1
Q
What are the main features of acute leukaemia (5)
A
A neoplastic condition characterised by: Rapid onset Early death if untreated Immature cells (blast cells) Bone marrow failure
2
Q
What are the clinical signs of bone marrow failure (3)
A
Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding
3
Q
Where cell do all blood cells originate
A
Pluripotent haemopoietic stem cell in the bone marrow
4
Q
What are the main cell types (8)
A
Erythroid lineage Megakaryocyte lineage Neutrophil lineage Monocyte lineage Eosinophil lineage Basophil lineage B cells T cells
5
Q
What cells are affected in chronic lymphoblastic leukaemia
A
B cells
6
Q
What cells are affected in acute lymphoblastic leukaemia
A
T cell precursors (T-ALL)
B cell precursors (B-ALL)
7
Q
What cells are affected in chronic myeloid leukaemia
A
Pluripotent haemopoietic stem cells
8
Q
What cells are affected in acute myeloid leukaemia
A
Multipotent myeloid stem cell/progenitor cell
9
Q
What is the dominant cell type in acute leukaemias
A
Blast cells
10
Q
Demographics of AML (3)
A
Increases with age
Prognosis worse with increasing age
40% of adults cured
11
Q
What are the chromosomal abnormalities that lead to leukaemias (5)
A
Duplication (usually trisomy) Loss Translocation Inversion Deletion
12
Q
What are the chromosomal translocations in AML (2)
A
T(15;17)
T(5;8)
13
Q
What is the chromosomal inversion in AML
A
Inv(16)
14
Q
What leukaemias tend to have new fusion genes (2)
A
AML
ALL
15
Q
What leukaemia tends to have abnormal regulation of genes
A
ALL
16
Q
What leukaemia can have chromosomal duplication
A
AML
17
Q
What are hotspot chromosomes for duplication in AML (2)
A
+8
+21
Dosage effect - extra copies of proto-oncogenes
18
Q
What leukaemia can have chromosomal loss or deletion
A
AML
19
Q
What are chromosomal hotspots for loss/deletion in leukaemia (2)
A
5/5q
7/7q
20
Q
How can chromosomal loss/deletion cause leukaemia (3)
A
Possible loss of tumour suppressor genes
Or…one copy of an allele may be insufficient for normal haemopoiesis
Possible loss of DNA repair systems
21
Q
What molecular abnormalities can occur in leukaemia (4)
A
Point mutation - NPM1, CEBPA
Loss of tumour suppressor genes
Partial duplication - FLT3
Cryptic deletion
22
Q
What effect does partial duplication of FLT3 have in leukaemia
A
Proliferation and survival effects
23
Q
What is the pathogenesis of most AML
A
Block of maturation of granulocyte
Accumulation of blast cells
24
Q
What is the characteristic cell of leukaemia
A
Blast cells
25
What are the risk factors for AML (5)
```
Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking
Unknown
```
26
What is the characteristic of leukaemogenesis in AML
Multiple genetic hits:
| At least 2 interacting molecular defects synergise to give leukaemic phenotype
27
What two abnormalities occur in leukaemogenesis in AML (2)
Type 1 abnormalities - promote proliferation and survival
| Type 2 abnormalities - block differentiation (which would normally be followed by apoptosis)
28
How is cell differentiation mediated
Transcription factors:
Bind to DNA
Alter structure to favour transcription
Regulate gene expression
If transcription factor function is disrupted, cells cannot differentiate
29
What proteins are involved in cell differentiation
Core binding factor:
Dimeric transcription factor
Master controller of haematopoiesis
30
What core binding factor abnormalities cause AML (2)
T(8;21) fuses RUNX1 (encoding CBFalpha) with RUNX1T1 - 15% of adult AML
Inv(16) fuses CBFB with MYH11 - 12% of adult AML
31
What is the histology in t(8;21) AML (2)
Some blast cells
| Some mature cells
32
What is the histology in Inv(16), t(16;16)
Some maturation to bizzarre eosinophil precursors with giant purple granules
33
What is important about t(15;17) acute promyelocytic leukaemia (8)
A very special type of acute leukaemia
The molecular mechanism is understood
Molecular treatment can be applied
The great majority of patients can now be cured
An excess of abnormal promyelocytes
Disseminated intravascular coagulation (DIC)
Two morphological variants but the same disease
34
When is maturation blocked in t(15;17) AML
Later than in other AML
35
What are the leukaemogenesis abnormalities in acute promuelocytic leukaemia (2)
Type 1 abnormalities - FLT3-ITD
Type 2 abnormalities - t(15;17) PML-RARA
36
What are the leukaemogenesis abnormalities in CBF leukaemias (2)
Type 1 abnormalities - sometimes mutated KIT
Type 2 abnormalities - mutation affecting function of CBF
37
How can you distinguish between AML and ALL (3)
Cytological features
Cytochemistry
Immunophenotyping
38
What stains are used for AML cytology (3)
Myeloperoxidase (positive reaction confirms myeloid cells)
Non-specific esterase
Sudan black B
39
What stains are used in ALL
None
40
What does immunophenotyping detect
Cell surface and cytoplasmic antigens
41
What are some forms of immunopheotyping (3)
Flow cytometry
Immunocytochemistry
Immunohistochemistry
42
When is flow cytometry used in leukaemia diagnosis
When samples are similar under microscopy
43
What are some ALL immunophenotype markers (3)
Precursor-B cell: CD19, CD20, TdT, CD10
B-cell: CD19, CD20, surface Ig
T-cell: CD2, CD3, CD4, CD8, TdT
44
What are some AML immunophenotype markers
```
MPO
CD13
CD33
CD14
CD15
Glycophorin (E)
Platelet antigens
```
45
What are some ALL and AML immunophenotype markers (3)
CD34
CD45
HLA-DR
46
Clinical features of AML (2)
Bone marrow failure
| Local infiltration
47
What are features of bone marrow failure (3)
Anaemia
Neutropenia
thrombocytopenia
48
What are some clinical features of local infiltration of AML (5)
```
Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy (only occasionally)
Skin, CNS or other sites
```
49
Skin infiltration, gum infiltration and organomegaly
AML
50
CNS disease
Particularly with monocytic differentiation (and ALL)
51
Clinical manifestation of bone marrow failure
Infection (chest, skin, soft tissue, may be severe and life threatening - septic shock, renal failure, DIC)
52
Clinical manifestation of thrombocytopenia
DIC
| Bleeding
53
What leukaemia can cause DIC
Acute promyelocytic leukaemia
54
Eye manifestations in AML (2)
Hyperviscosity if WBC is very high
Retinal haemorrhages
Retinal exudates
55
How is AML diagnosed
Blood film usually diagnostic
56
What are the blood film features in AML (2)
```
Circulating blasts
Aurer rods (proves myeloid)
```
57
How can you tell the difference between AML and ALL if no blood film signs
Immunophenotyping
58
How do you diagnose leukaemia if there are no leukaemic cells in the blood
Bone marrow aspirate
59
Diagnostic methods for AML (2)
Blood films
| Bone marrow aspirate
60
What is the point of cytogenetic and molecualr studies/FISH in AML
Prognostic value and helps select treatment
61
Good prognostic cytogenetics in AML (3)
T(15;17)
T(8;21)
Inv(16)
62
What are the two treatment strategies for AML (2)
Supportive care
| Chemotherapy
63
What is involved in supportive care for AML (6)
Red cells
Platelets
Fresh frozen plasma/cryoprecipitate if DIC
Antibiotics
long line
Allopurinol, fluid and electrolyte balance
64
What does chemotherapy do to cells
Damages DNA
65
How does chemotherapy work
Normal stem cells - often quiescent, checkpoints allow repair of DNA damage
Leukaemia cells - continously dividing, lack of cell cycle checkpoint control
66
What is the point of combination chemotherapy (3)
Different mechanisms of action
Synergy
Non-overlapping toxicity IMPORTANT
67
What is the chemotherapy treatment for AML (4)
Mainly cell cycle specific drugs
4-5 courses (remission induction x 2, consolidation x 2-3)
About 6 months of therapy
Consider transplantation if poor prognosis
68
Why have results of treatment of AML improved (3)
Better supportive care
Identification of bad prognosis groups for more intensive treatment (more intensive chemotherapy or transplantation)
Specific treatment for acute promyelocytic leukaemia
69
Features of ALL (4)
Peak incidence in childhood
Most common childhood malignancy
85% of children cured
Prognosis worse with increasing age
70
What is prognosis dependent on in AML (6)
```
Patient characteristics
Morphology
Immunophenotyping
Cytogenetics
Genetics
Response to treatment
```
71
Clinical features of ALL (2)
Bone marrow failure: anaemia, neutropenia, thrombocytopenia
Local infiltration: lymphadenopathy (+/- thymic enlargement), splenomegaly, hepatomegaly, testes, CNS, kidneys or other sites, bone (causing paiN)
72
Blood film in ALL (4)
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts
73
Bone marrow in ALL
Lymphoblast infiltration - may be B or T cell lineage
74
Difference between B lineage or T lineage ALL
B lineage - starts in the bone marrow
T lineage - starts in the thymus and thymus may be enlarged
Genetics different
75
Genetic features of ALL (4)
As for AML, prognosis is very dependent on cytogenetic/genetic subgroups, particularly for B lineage ALL Hyperdipoidy, t(12;21), t(1;19) – good prognosis
T(4;11), hypodiploidy – poor prognosis
T(9;22) – improved prognosis with tyrosine kinase inhibitors
76
Good prognosis genetics ALL (3)
Hyperdiploidy
T(12;21)
T(1;19)
77
Poor prognosis ALL (2)
T(4;11)
| Hyperdiploidy
78
How does proto-oncogene dysregulation occur in ALL (leukaemogenic mechanisms)
Chromosonal translocation (fusion genes, wrogn gene promoter, dysregulation by proximity to T cell receptor (TCR) or immunoglobulin heavy chain loci)
79
What is the philadelphia chromosome
T(9;22) - in ALL
bcr-abl gene in chromosome 22
80
Diagnosis of ALL (6)
```
Clinical suspicion
Blood count and film
Bone marrow aspirate
Immunophenotyping
Cytogenetic/molecular genetic analysis
Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
```
81
Why is immunophenotype of leukaemia matter (2)
AML and ALL are treated differently
| T lineage ALL and B lineage ALL are treated differently
82
Why is cytogenetic/molecular genetic category important in ALL treatment (2)
Ph-positive needs imatinib
| Treatment must be tailored to the prognosis
83
General principles of ALL treatment (2)
Specific therapy
| Supportive care
84
Specific therapy in ALL (2)
Systemic chemotherapy
| CNS directed therapy
85
Supportive treatment in ALL (9)
Central venous catheter
Red blood cell and platelet transfusions
Broad spectrum antibiotics for fever
Prophylaxis for Pneumocystis jirovecii infection
Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase
Hyperphosphataemia; aluminum hydroxide, calcium
Hyperkalemia: fluids, diuretics
Extreme leukocytosis (WBC > 200 × 109/l): leukapheresis
Sometimes haemodialysis
86
Chemotherapy for ALL features (6)
```
Induction cycle
Intensification/consolidation cycles
Early intrathecal chemotherapy for all (to treat occult CNS disease)
Prolonged continuation/maintenance phase
Two to three years of therapy
Special measures for poor prognosis
```
87
How long is ALL chemotherapy treatment in boys and girls (2)
2 years in girls
| 3 years in boys
88
CNS therapy for ALL key features (4)
Intrathecal chemotherapy even if initial LP is negative (6‒8 treatments)
More frequent, intensive and prolonged intrathecal chemotherapy for patients with lymphoblasts in CSF
Systemic chemotherapy that penetrates CNS (e.g. high dose cytarabine)
Cranial irradiation now less frequently used
89
Why is cranial irradiation less frequently used for ALL treatment
It causes cognitive impairment
Now that more children are cured, thinking about long term morbidity of treatment is increasingly important
90
ALL treatment results in children
5 year disease free survival 80%
91
ALL treatment results in adults
5 year disease free survival 30-40%
