Acute Leukaemia Flashcards
Give 4 features of acute leukaemia
Rapid onset
Early death if untreated
Immature cells (blast cells) replace normal tissue
BM failure:
- Anaemia: Fatigue, pallor, breathlessness
- Neutropenia: Infections
- Thrombocytopenia: Bleeding
What are features of acute myeloid leukaemia?
Increases with age
Prognosis worse with increasing age
40% of adults cured
Aberrations in Chr count/ structure
Which chromosomal translocations are associated with acute myeloid leukaemia?
t(15;17)
t(5;8)
Which chromosomal inversion is associated with acute myeloid leukaemia?
Inv (16)
What results from chromosomal translocations and inversions in acute leukaemia?
Altered DNA sequence
Creation of new fusion gene (AML + ALL)
Abnormal regulation of genes (mainly ALL)
What is the association between chromosomal duplication and AML?
Common in AML
Disease hotspots: +8 and +21 give predisposition
Possible dosage effect: extra copies of proto-oncogenes
Distinguish between an oncogene and protooncogene
Onco: Can contribute to neoplastic condition
Proto: potential to develop into oncogene
Most people use the term oncogene to describe both
What is the association between chromosomal loss or deletion and AML?
Common in AML
Disease hotspots: Deletions + loss of 5/5q + 7/7q
Possible loss of tumour suppressor genes.
Alternative explanation: 1 copy of an allele may be insufficient for normal haemopoiesis. Possible loss of DNA repair systems.
What are the molecular abnormalities in patients with apparently normal chromosomes which can result in AML?
Point mutation: NPM1, CEBPA
Loss of tumour suppressor genes
Partial duplication: FLT3
Cryptic deletion
Where does the block in maturation usually arise in AML?
Between myeloblast + pro-myelocyte
Proliferation continues
Increased blasts
What are 5 risk factors for AML?
Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking
Unknown
What is leukaemogenesis in AML?
Multiple genetic hits
At least 2 interacting molecular defects
Synergise to give leukaemic phenotype
What are the two types of abnormalities in leukaemogenesis in AML?
Type 1: Promote proliferation + survival.
Type 2: Block differentiation (which would normally be followed by apoptosis).
How is differentiation affected in AML?
Transcription factors:
Bind to DNA
Alter structure to favour transcription
Regulate gene expression
If TF function is disrupted, cells can’t differentiate.
What can be seen in t(8,21) AML?
Some maturation; not all blast cells.
Failure of adequate differentiation, not complete block
What can be see in inv(16), t(16;16) AML?
Some maturation to bizarre eosinophil precursors with giant purple granules.
What can be seen in acute promyelocytic leukaemia with t(15;17)?
Excess of abnormal promyelocytes.
Disseminated intravascular coagulation (DIC).
2 morphological variants but the same disease.
Molecular mechanism is understood, thus molecular tx can be applied.
Majority of patients can be cured.
What are the two types of abnormalities in acute promyelocytic leukaemia?
T1: FLT3 -ITD
T2: t(15;17) PML-RARA
What are abnormalities in leukaemogenesis in CBF leukaemias?
T1: Sometimes mutated KIT
T2: Mutation affecting function of CBF
(core binding factor)
What is the difference between cytochemistry between AML and ALL?
AML: Stain +ve for Myeloperoxidase (Gr), Sudan black (Gr) + Non-specific esterase (Mo)
ALL: -ve
What can be used if cytochemistry does not differentiate between AML and ALL?
Immunophenotyping:
Cell surface and cytoplasmic antigens
- Flow cytometry
- Immunocytochemistry: antibodies to cells on slide
- Immunohistochemistry: antibodies to tissue sections
What immunophenotypes are associated with ALL?
B-cell: CD19, CD20, TdT, CD10 +/-
T-cell: CD2, CD3, CD4, CD8, TdT
(TdT only in immature blast cells)
What immunophenotypes are associated with AML?
MPO (Myeloperoxidase)
CD13
CD33
CD14
CD15
Glycophorin (Erythroid)
Platelet antigens
What immunophenotypes are associated with both ALL and AML?
CD34 (Immature)
CD45 (Common leukocyte antigen)
HLA-DR
What are 8 clinical features of AML?
Bone marrow failure:
Anaemia: pallor, fatigue
Neutropenia: infection: septic shock
Thrombocytopenia: bleeding, DIC
Local infiltration:
Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy (occasionally, ALL>AML)
Skin, CNS, other sites
How is AML diagnosed?
Blood film:
- Usually diagnostic: circulating blasts
- Auer rods (proves myeloid)
- “Aleukaemic” leukaemia: If no leukaemic cells in in blood, need a BM aspirate.
- Cytogenetic studies
- +/- Molecular studies + FISH
Give 4 characteristics of ALL
Peak incidence in childhood.
Most common childhood malignancy.
85% of children cured.
Prognosis worse with increasing age.
What are 8 clinical features of ALL?
Bone marrow failure:
Anaemia
Neutropenia
Thrombocytopenia
Local infiltration:
Lymphadenopathy (± thymic enlargement)
Splenomegaly
Hepatomegaly
Testes, CNS, kidneys, other sites
Bone (causing pain)
What are 6 pathological features of ALL?
Peripheral blood:
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts
BM + other tissues:
Lymphoblast infiltration
Lymphoblasts may be B-lineage or T-lineage
How do the genetic factors contribute to the prognosis of ALL?
Prognosis very dependent on cytogenetic/ genetic subgroups, esp. for B-lineage ALL.
Hyperdiploidy, t(12;21), t(1;19) = good
t(4;11), hypodiploidy = poor
t(9;22) = improved with tyrosine kinase inhibitors
What are the leukaeomogenic mechanisms of ALL?
Proto-oncogene dysregulation: chr translocation
- Fusion genes
- Wrong gene promoter
- Dysregulation by proximity to T-cell receptor (TCR) or immunoglobulin heavy chain loci
Unknown: hyperdiploidy
How is ALL diagnosed?
Clinical suspicion
Blood count + film
BM aspirate
Immunophenotyping
Cytogenetic/ molecular genetic analysis
Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
From which cells do the leukaemias arise?
AML: Pluripotent haematopoeitic, multipatent myelolid, GM precursor
CML: Pluripotent haematopoeitic (potential for lymphoid differentiation)
B ALL: cells committed to B lineage
T ALL: cells committed to T lineage
CLL: Mature B cells
Summarise the leukaemogenesis in AML
Multiple genetic hits: Chr translocation, loss of genetic material, mutation of genes
Proliferation + survival encouraged
Differentiation blocked
Cells don’t die normally
Name 2 cytological features of AML
Auer rods
Granules
What ocular manifestation may arise in AML?
Retinal haemorrhages + retinal exudates if WBC is very high due to hyperviscosity
How can you tell ALL versus AML if there are no granules or Auer rods circulating? Why is the result important?
Immunophenotyping
AML + ALL are treated v differently
T (15%) + B (85%) ALL may be treated differently
From which site is a bone marrow aspirate taken?
Posterior superior iliac crest
Describe the treatment of AML
Supportive: Red cells, Platelets, FFP, Abx, Long line, Allopurinol, Fluids
Chemo
Targeted molecular therapy
Transplantation
Why is allopurinol given to patients being treated for AML?
Due to precipitation of uric acid once tumour cells start to break down
How does chemotherapy preferentially target leukaemic cells?
Normal stem cells often quiescent + checkpoints allow repair of DNA damage
Leukaemic cells continuously dividing + lack of cell cycle checkpoint control
What molecular targeted therapy is available for acute promyelocytic leukaemia?
All-trans-retinoic acid (ATRA)
Arsenic trioxide (A2O3)
How do B and T lineage ALL pathological features differ?
B: starts in BM
T: can start in thymus, thymus may be enlarged
Why does cytogenetic/ molecular genetic category matter in diagnosis of ALL?
Ph +ve need Imatinib
Tx must be tailored to prognosis
Describe the treatment of ALL
Systemic chemo
CNS-directed therapy
Molecular targeted tx
Transplantation
Supportive: blood products, abx
