Acute Leukaemia Flashcards
1
Q
What is acute leukaemia characterised by?
A
o Rapid onset
o Early death if untreated (weeks or months)
o Immature cells (blasts)
o Bone marrow failure
anaemia (pallor, fatigue, SoB),
neutropoenia (infections),
thrombocytopaenia (bleeding)
2
Q
Where do the mutations occur in leukaemia?
A
• The leukaemias arise due to the presence of mutations at various point in the B and T cell lineages
• CML occurs at the pluripotent haemopoietic stem cell level because during the chronic phase it is characterised by overproduction of myelocytes, however, when it turns acute, it can then have a lymphoblastic crisis
o I.E. CML ALL blast crisis
• AML can also occur at a pluripotent haemopoietic stem cell level meaning that it presents as a myeloid leukaemia but then relapse later on as an acute lymphoid leukaemia
o I.E. AML ALL many years later in relapse
• Other AMLs can occur at a multipotent stem cell level or a granulocyte-monocyte precursor level
3
Q
When do AML present
A
4
Q
What chromosomal abnormalities can you get in AML?
A
5
Q
Describe chromosomal translocation?
A
oInversion or translocations (alters the DNA sequence)
- Creates new fusion genes ALL and AML
• Acute Myeloid Leukaemia / AML; t (8; 21) -> RUNX1+RUNX1T1 15% of AML
o Partial block – some mature cells remain
• Core Binding Factor – AML / CBF-AML; Inv (16), t (16; 16) -> fusion gene 12% of AML
o Partial block – some mature ‘eosinophil-type’ cells remain
• Acute Promyelocytic Leukaemia / APML; t (15; 17) -> PML-RARA APML - Abnormally regulates genes ALL
6
Q
Describe chromosomal duplication
A
- Common in AML
- Trisomy 8 and Trisomy 21 (gives a predisposition to AML → as seen in TAM in Down’s syndrome)
- There is a possible dosage effect associated with these trisomy’s (having 3 copies of a proto-oncogene rather than 2 may be the underlying trigger of the leukaemia)
7
Q
Describe chromosomal loss and deletion.
A
- Common in AML
- MOST COMMON = del (5q) or del (7q)
- Leukaemogenesis from…
- Due to loss of tumour suppressor gene
- One copy of an allele may be insufficient for normal haemopoiesis
- Possible loss of DNA repair systems
8
Q
What molecular abnormalities can occur in chromosomes?
A
- Point mutations (associated with AML) → prognostic implications
- Loss of function of tumour suppressor genes
- Partial duplication
- Cryptic deletion (fusion gene forms deletion of tiny bit of DNA and remaining ends joining up)
9
Q
How does maturation differ in AML?
A
Excess of myeloblasts
10
Q
A
AML
11
Q
Why do people get AML?
A
- Familial or constitutional predisposition (e.g. Down syndrome)
- Irradiation
- Anticancer drugs
- Cigarette smoking
- Unknown
12
Q
How does laeukamogenesis occur in AML?
A
13
Q
What are the 2 types of abnormalities in AML?
A
14
Q
How does differentiation occur?
A
- Transcription factors are very important in differentiation as they:
- Bind to DNA
- Alter structure to favour transcription
- Regulate gene expression
- Thus, disruption of transcription factor function can result in failure of differentiation – 2 examples:
- (1) t(8; 21)
- (2) inv(16)
-
Core Binding Factors are…
- Dimeric transcription factor
- Master controllers of haemopoiesis
- Thus, disruption of transcription factor function can result in failure of differentiation – 2 examples:
15
Q
What happens in core binding factor leukaemia?
A
16
Q
What happens in core binding factor leukaemia?
A
17
Q
A
t(8;21) - some maturation
18
Q
Describe the inversion blocking differentiation in AML?
A
19
Q
Describe acute promyelocytic leukaemia with t(15;17)
A
- Pathophysiology = t (15; 17) → PML-RARA fusion gene
- Causes haemorrhage (e.g. sudden onset bruising or bleeding) – exhibits DIC and hyperactive fibrinolysis
- Slightly later block in maturation than in classic AML
- Most patient can be cured as molecular mechanism understood
- Characterised by an excess of abnormal promyelocytes (Auer rods)
20
Q
Where does the maturation defect occur in t(15;17)
A
21
Q
What are the 2 morphological forms of acute promyelocytic leukaemia?
A
- There are two morphological variants but the same phenotypic disease and molecular patterns
- Variant form = granules still present at resolution below that of a light microscope so can’t see all of them
- Variant form is characterised by bilobed nuclei
22
Q
What are the 2 mutations in acute promyelocytic leukaemia?
A
23
Q
What are the 2 mutations in CBF leukaemia?
A
24
Q
How do you know if it is AML or ALL?
A
- Cytological features
- Cytochemistry
- Immunophenotyping
25
What difference would you find on investigations?
26
What are the clinical features of AML?
* Bone marrow failure (anaemia, neutropoenia/infection, thrombocytopaenia)
* RBCs → SoB, pallor, anaemia
* WCC → infections
* Platelets → bleeding and bruising (APML → haemorrhage as fibrinolysis upregulated)
* Local infiltration:
* Splenomegaly
* Hepatomegaly
* Gum infiltration (**monocytic** leukaemia; i.e. APML)
* Skin, CNS or other sites (**monocytic** leukaemia; i.e. APML) – i.e. cranial nerve palsies
* Lymphadenopathy (occasionally – more in **lymphomas**)
* Hyperviscosity if WBC is very high → retinal haemorrhages or retinal exudates
27
What can be the complications of bone marrow failure infection in AML?
* May be severe and life threatening
* septic shcok
* renal failure
* DIC
28
How dose diagnose AML?
* Blood count, blood film and BM aspirate → diagnostic with presence of circulating blasts ± cytochemistry\*
* **Auer** rods = AML; presence of **granules** = AML
* If neither… use **immunophenotyping** to determine AML vs ALL
* **Aleukaemic leukaemia** (i.e. no peripheral blood leukaemic cells → need to do a BM aspirate)
* Cytogenetic studies (all newly diagnosed patients)
* Immunophenotyping (immunohistochemistry, immunocytochemistry → determine AML from ALL)
* Molecular studies and FISH (some patients) → enable _sub-classification_ of the acute myeloid leukaemia and adds _prognostic value_ and aids _treatment_ decisions (certain cytogenetic findings aid prognosis)
29
How do we treated AML?
* **(1)** Supportive
* Red cells
* Platelets
* FFP/cryoprecipitate if DIC
* Antibiotics
* Long line
* Allopurinol, fluid and electrolyte balance
* **(2)** Chemotherapy:
* **(3)** Targeted molecular therapy:
* **(4)** Transplantation
30
What does chemotherapy entail?
* Damage DNA of leukaemic cells → target continuously dividing cells that lack cell cycle checkpoint control
* Combination chemotherapy:
* Different mechanisms of action that work in synergy
* Important to ensure non-overlapping toxicity
31
How long do you give chemotherapy for?
* Treatment:
* Cell-cycle specific drugs
* 4-5 courses (remission induction x2; consolidation x2-3)
* After 6 months stop, but consider transplantation if poor prognosis
32
What does targeted molecular therapy entail?
* **APML** = All-trans-retinoic acid (ATRA) and A2O3
* **Ph +ve** (**CML**, but also rare AML cases) = tyrosine kinase inhibitors
* **Biologics** = anti-CD33 antibody linked to cytotoxic antibody (e.g. gemtuzumab)
* Drugs targeting products of other mutated genes
* Antibody tx e.g. gentuzumab, ozogamicin, a cytotoxic antibiotic linked to an anti-CD33 antibody
33
* Why have the results of AML treatment improved?
* Better supportive care
* Identification of poor prognosis groups
* Specific treatment for APML
34
What are determinants of prognosis in AML?
* **Patient characteristics**
* Morphology
* Immunophenotyping
* **Cytogenetics**
* **Genetics**
* Response to treatment
35
When does ALL present?
* Peak incidence in childhood (**MOST COMMON** childhood malignancy 85% of children are cured)
* Prognosis is worse with increasing age
36
What are the clinical features of ALL?
* Signs and symptoms:
* Bone marrow failure (anaemia, thrombocytopenia, neutropoenia)
* Local infiltration
* **Lymphadenopathy** (± thymic enlargement)
* Splenomegaly
* Hepatomegaly
* Testes, CNS (these are **‘sanctuary sites’** as chemotherapy cannot reach them easily)
* Bone (causing pain)
37
What are the pathological features of ALL?
* Peripheral blood (blood film) → anaemia, neutropoenia, thrombocytopaenia, **lymphoblasts**
* Bone marrow → **lymphoblastic infiltration** (B- or T-lineage – _different genetic defects predispose_ to each)
* B-Lineage ALL
* Starts in the Bone marrow
* T-Lineage ALL
* Start in the Thymus (which may be enlarged)
38
What are the genetic features of ALL?
* Prognosis is very dependent on cytogenetic/genetic subgroups (particularly for B-lineage)
* GOOD Prognosis:
* **Hyperdiploidy** t(12;21) t(1;19) TK inhibitors (Ph +ve; t(9; 22)
* POOR Prognosis:
* t(4;11) Hypodiploidy (before TKI, Ph +ve)
39
What are the leukaemogenic mechanisms in ALL?
* Proto-oncogene dysregulation → chromosomal translocation:
* Fusion genes
* Wrong gene promoter
* Dysregulation by proximity to TCR or immunoglobulin heavy chain loci
* Unknown – hyperdiploidy
40
How do we diagnose ALL?
* Clinical suspicion
* Blood count and film
* Bone marrow aspirate
* Immunophenotyping (diagnostic) – this is very important because…
* AML and ALL are treated very differently
* Moreover, B-lineage (85%) and T-lineage (15%) are treated very differently
* Cytogenetic/molecular genetic analysis – this is very important because…
* Philadelphia chromosome +ve needs **imatinib**
* Treatment tailored to prognosis (intensify treatment if bad prognosis)
* Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
41
How do we treat ALL?
* **(1)** Supportive:
* Blood products
* Antibiotics (broad-spectrum for fever; prophylaxis for PCP infection)
* General medical care
* Central venous catheter Hyperuricaemia management
* Hyperkalaemia management Sometimes haemodialysis
* **(2)** Chemotherapy (systemic + CNS-intrathecal-specific):
* Systemic = 2-3 years of therapy (induction and consolidation):
* Boys treated for longer because testes are a site of accumulation of lymphoblasts
* CNS-specific (done in all patients even if initial LP is negative):
* Can also be done by giving **high-dose chemotherapy** so that it penetrates the BBB
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* **(3)** Molecular treatment:
* TKI for Ph +ve cases
* Rituximab (monoclonal antibodies against CD20)
* **(4)** Transplantation
