Haem: Acute Leukaemia Flashcards
Explain the cell lineage of pluripotent haematopoietic stem cells
pluripotent haematopoietic stem cells can give rise to lymphoid or myeloid stem cells.
Myeloid cells differentiate into megakaryocytes-erythrocytes cells OR granulocytes-monocyte cells.
Lymphoid cells differentiate into B or T cells
Which cells does AML manifest with?
Any of the cells of myeloid lineage
Which cells does CML manifest with?
Chronic phase - Myeloid cells
Acute phase - Lymphoblastic crisis (Particularly B cells)
CML occurs in a pluripotent haematopoietic stem cell
What do blast cells typically look like?
High nucleus : cytoplasm
Diffuse chromosome pattern
What type of chromosome abnormalities are seen in AML?
Duplication (trisomy) - Cr 8 and 21 (As seen in Down’s syndrome too)
Loss - Possibly of Tumour suppressor genes or Cr repair systems
Translocation
Deletion of part of a chromosome
Point mutations - NPM1 (Good prognosis) and CEBPA (Good prognosis if both copies are mutated)
Partial duplication (FLT3 which is a bad prognosis)
Cryptic deletion
What type of chromosome abnormalities are seen in ALL?
Translocation leading to abnormal regulation of genes and creation of new fusion genes
What are the normal granulocyte maturation stages?
Myeloblast 🡪 promyelocyte 🡪 myelocyte 🡪 metamyelocyte 🡪 band form 🡪 neutrophil
How does the normal granulocyte maturation process differ in AML?
Differentiation of the cells is disrupted, leading to accumulation of blast (immature) cells
What is necessary for Leukaemogenesis in AML
Multiple genetic hits
What are type 1 abnormalities
Mutation promotes proliferation and survival (anti-apoptosis)
What are type 2 abnormalities
Block differentiation (which would normally be followed by apoptosis) This leads to an accumulation of blast cells
Explain how leukaemogenesis can happen in2 ways in Core Binding factor (CBF)?
Translocation of 8:21 leads to partial block in differentiation (mixture of mature and blast cells)
Inversion of Cr 16 leads to arrest in differentiation leading to some cells to mature into bizarre eosinophil precursors
How many blast cells is needed to call the malignancy acute leukaemia?
20% of the blast cells
What is the dominant negative effect?
when a single abnormal chromosome dominates over the normal one
What is APML?
It is characterised by an excess of abnormal promyelocytes
How does APML present?
DIC and hyperactive fibrinolysis - Haemorrhage, low platelet
Acute presentation and is a medical emergency
What causes APML?
Translocation between Cr 15 and 17 forming the PML-RARA fusion gene
What can you see on a blood film with APML?
Auer rods - Promyelocytes
What can you see on the blood film of of the APML variant?
Bilobed nuclei
What are the type 1 and 2 mutations in APML?
Type 1 mutation: FLT3-ITD – this makes the prognosis worse
Type 2 mutation: PML-RARA
What are the type 1 and 2 mutations in CBF leukaemias?
Type 1 mutation: sometimes mutated KIT
Type 2 mutation: mutation affecting function of CBF
How is APML treated?
By targeting the molecular mechanism, you unblock the blocked differentiation and the leukaemic clone matures into end cells which then die
How to differentiate between AML and ALL?
Auer rods - Myeloid Granulocytes - Myeloid Myeloperoxidase stain - Myeloid Sudan Black - Myeloid Non-specific esterase stain - Myeloid
Absence of all if this means ALL lol
What does the presence of TdT and/or CD34 indicate?
Primitive cell (non lineage specific)
What are the clinical features of bone marrow failure in AML?
Anaemia
Neutropaenia - Infections, necrotising fascitis, sepsis
Thrombocytopaenia- bruising, bleeding
DIC - Pinpoint petachiae or echymosis or peripheral vessel obstruction or gangreen
What are the clinical features of local infiltration in AML?
Splenomegaly
Hepatomegaly
Gum infiltration (if it is a monocytic lineage)
Lymphadenopathy (only occasionally)
Skin, CNS or other sites
Can cause cranial nerve palsies
This can occur as a result of meningeal infiltration
Hyperviscosity if WBC is very high
This can cause retinal haemorrhages or retinal exudates
How is AML diagnosed?
Blood film - Circulating blasts, auer rods, presence of granules
Immunophenotyping
Aleukaemic leukaemia
What is Aleukaemic leukaemia
This is when there are NO leukaemic cells in the peripheral blood but the bone marrow has been replaced
How is AML treated?
RBCs Platelets FFP/ cryoprecipitate if DIC Antibiotics Long line inserted into a central vein Allopurinol (to prevent uric acid production to prevent AKI) Fluid and electrolyte balance Chemotherapy Targeted molecular therapy Transplantation
What are targets of chemo treatment?
Damage the DNA of the leukaemic cells
Leave the normal stem cells unaffected
How to treat Philadelphia Cr positive cases?
Tyrosine kinase inhibitors
How common is ALL in kids and do they tend to be Philadelphia Cr positive in kids?
MOST COMMON childhood malignancy
chances of it being Philadelphia Cr positive increases with age
What are the clinical features of ALL?
Bone marrow failure Anaemia Neutropaenia Thrombocytopaenia Local infiltration Lymphadenopathy (+/- thymic enlargement) Splenomegaly Hepatomegaly Testes, CNS, kidneys or other sites Bone (causing pain)
What would you find in a blood film in ALL?
Anaemia
Neutropaenia
Thrombocytopaenia
Usually lymphoblasts - Only supposed to be found in the bone marrow
What genetic picture is good prognosis in ALL?
Hyperdiploidy
t(12;21)
t(1;19)
t(9;22)- this is the Philadelphia chromosome
What genetic picture is poor prognosis in ALL?
t(4;11)
Hypodiploidy
In general what are the symptoms of ALL in kids?
bone pain, limping, pallor, bruising, organomegaly
