Myeloid Malignancy Flashcards
Where do mutational events occur leading to myeloid malignancies?
In haematopoietic stem cell or in the early (more committed) myeloprogenitor cell
A mutation in the haemopoetic stem cell leading to leukaemia produced a cell called what?
Leukaemic stem cell
What are the two vital jobs of the HPSC?
Self-renewal and multipotentiality
How is self-renewal different in AML?
Early progenitor cells should lose their ability to self-renew in health, but instead they behave more like stem cells due to mutations and are able to self-renew
BUT differentiate is blocked –> population grows replacing the normal haematopoietic stem cells
What are the features of AML?
Bone marrow failure
anaemia, thrombocytopenic bleeding (purpura/mucosal membrane), infection (due to neutropenia, mostly bacterial/fungal
What is the appearance of the bone marrow in acute leukaemia?
Absolutely packed with blast cells (buried within this are leukaemic stem cells driving this)
What is a big confluent area of thrombocytopenic bleeding in the skin called?
Ecchymosis
What investigations should you do if you suspect AML?
Blood count, blood film (WCC high/low, neutropenia, thrombocytopenia, low Hb)
Bone marrow aspirate (will confirm diagnosis)/trephine
Cryptogenetics (karyotype) from leukaemic balsts
Immunophenotyping of leukaemic blasts (can distinguish between myeloblasts/lymphoblasts)
CSF examination if symptoms (e.g. headache, cranial n palsy)
Targeted molecular genetics for associated acquired gene mutations
What must you see on bone marrow aspiration to confirm AML diagnosis?
> 20% blasts
What associated acquired gene mutations might you test for?
FLT3 (poor prognosis), NPM1 (better prognosis), IDH 1 and 2 (enzymes of kreb cycle that can become leukogenic)
How do you treat AML?
Supportive care (platelets, transfusion, antibx, antifungals if needed etc.)
Anti-leukaemic chemotherapy (induction and consolidation)
Use danorubicin and cytosine arabinoside
Allogenic stem cell transplantation (recognises leukaemia as foreign and kills it)
All-trans retinoic acid and arsenic trioxide in low risk acute promyelocytic leukaemia
What targeted treatments can be used for AML?
Midostaurin in FLT3 mutated AML
What is the new targeted antibody treatment in AML?
Mylotarg
Binds to CD33 antigen on leukaemic cells, if internalised and releases molecules that damage DNA
But drug pump on leukaemic cell can release these –> damage to other cells
What is chronic myeloid leukaemia?
Mutation in HPSC with excessive proliferation in the myeloid lineage (esp granulocytes)
What are the features of CML?
Anaemia (bone marrow failure, cytokine supressing haemostasis, hepicidin)
Splenomegaly (due to infiltration)
Weight loss (sweat a lot due to huge cell burden)
Hyperleukostasis - fundal haemorrhage, venous congestion, altered consciousness, respiratory failure
Gout
Why must you not transfuse blood in CML patients?
Anaemia is protective as there is hyperleukostasis
What would be a typical blood count in CML?
High WBC, low Hb, often high platelets, high neutrophils and monocytes, eosinophils, basophils etc.
What is the appearance of the blood film in CML?
lots of white cells, with myelocytes and metamyelocytes
What are the lab features of CML?
High WCC, platelets, anaemia, blood film with all stages of white cell differentiation with increased basophils
Bone marrow hypercellular
Philadelphia chromosome present
What is the Philadelphia chromosome?
A translocation between chromosome 9 and 11 leading to a BCR-ABL fusion which is present in a lot of CML
What is involved in the treatment of CML?
Tyrosine kinase inhibitors, e.g. glivec
(direct inhibitors of the BCR-ABL gene)
Allogenic transplantation in TKI failure
How do the tyrosine kinase inhibitors work?
ABL-BCR gene activates downstream uncontrolled downstream signalling through phospholyation but the TKIs bind to the kinase domain and block CML essentially
What are myelodysplastic syndromes?
Acquired clonal disorders of bone marrow
Seen in elderly
What is the typical presentation of MDS?
Elderly, may present as macrocytic anaemia and pancytopenia
