Acute Leukaemia Flashcards
What is acute leukaemia characterised by?
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)
Where do the mutations occur in leukaemia?
• 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
When do AML present
What chromosomal abnormalities can you get in AML?
Describe chromosomal translocation?
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
Describe chromosomal duplication
- 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)
Describe chromosomal loss and deletion.
- 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
What molecular abnormalities can occur in chromosomes?
- 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)
How does maturation differ in AML?
Excess of myeloblasts
AML
Why do people get AML?
- Familial or constitutional predisposition (e.g. Down syndrome)
- Irradiation
- Anticancer drugs
- Cigarette smoking
- Unknown
How does laeukamogenesis occur in AML?
What are the 2 types of abnormalities in AML?
How does differentiation occur?
- 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:
What happens in core binding factor leukaemia?
What happens in core binding factor leukaemia?
t(8;21) - some maturation
Describe the inversion blocking differentiation in AML?
Describe acute promyelocytic leukaemia with t(15;17)
- 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)
Where does the maturation defect occur in t(15;17)
What are the 2 morphological forms of acute promyelocytic leukaemia?
- 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
What are the 2 mutations in acute promyelocytic leukaemia?
What are the 2 mutations in CBF leukaemia?
How do you know if it is AML or ALL?
- Cytological features
- Cytochemistry
- Immunophenotyping
What difference would you find on investigations?
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
What can be the complications of bone marrow failure infection in AML?
- May be severe and life threatening
- septic shcok
- renal failure
- DIC
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)
-
Auer rods = AML; presence of granules = AML
- 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)
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
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
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
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
- Why have the results of AML treatment improved?
- Better supportive care
- Identification of poor prognosis groups
- Specific treatment for APML
What are determinants of prognosis in AML?
- Patient characteristics
- Morphology
- Immunophenotyping
- Cytogenetics
- Genetics
- Response to treatment
When does ALL present?
- Peak incidence in childhood (MOST COMMON childhood malignancy 85% of children are cured)
- Prognosis is worse with increasing age
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)
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)
- B-Lineage ALL
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)
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
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
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
- Systemic = 2-3 years of therapy (induction and consolidation):
-
(3) Molecular treatment:
- TKI for Ph +ve cases
- Rituximab (monoclonal antibodies against CD20)
- (4) Transplantation
