Ha - CML / Myeloproliferative Disorders Flashcards
Normal haumatopoeisis is regulated by…?What do they interact with?
Growth factors.
These interact with receptors –> tyrosine kinase activation
Important enzymes in haematopoeisis? How does mutation affect this?
Janus Kinases
Mutation –> they become constitutively active –> aberrant cell proliferation
2 mutations seen in MPNs?
JAK2 V617F mutation
Exon 12 mutation
Name 3 myeloproliferative neoplasia which are BCR-ABL negative?
Essential thrombocytosis
Polycythemia Rubra Vera
Myelofibrosis
2 main features of MPNs?
Common presentations?
- Assoc with BM fibrosis
- Increased proliferation of mature cells
How does blood from MPN patients behave on agar culture?
Cells will grow in absence of EPO or TPO
Diagnostic for PCV?
Increased RBCs + JAK2 V617 mutation
Epidemiology for PCV - age? sex?
M>F
Generally 60yos
Sx of PCV?
Hyper viscosity: headaches, dizziness, stroke, retinal vessel engorgement, visual disturbance, fatigue
Histamine release: AQUAGENIC PRURITIS. peptic ulcers
Gout
Haem Ix with results in PCV?
High Hb + Hct + MCV
Often high Plts + WCC
Plasma volume high (from isotope dilution method)
Low EPO
Aim of PCV Mx? how is this achieved?
Hct<45% + Plt <400x10^9
- Venesection + cytoreductive therapy
- aspirin + hydroxycarbamide
Dx if pt has raised HCt with an JAK2 Exon 12 mutation?
Idiopathic erythrocytosis
Features of idiopathic erythrocytosis?
Genetics?
Tx?
- Isolated raised RBCs
- No V617F mutation - often have exon 12 mutation
- Managed with venesection alone
What is the disorder?
- 2 age peaks at 30 and 55 yo
- BM dominated by megakaryocytes
- Blood film = large platelets
- Plt count >600*10^9
Essential thrombocytosis
Genetics in essential thrombocytosis
- 50% have JAK2 mutation therefore difficult to diagnose in absence of mutation
- Some have TPO receptor mutation
Clinical features of essential thrombocytosis
-Thrombosis (stroke/MI/gangrene/haemorrhage)
-Dizziness, headaches, visual
- splenomegaly
- WEIRDLY, BLEEDING
Ix results in essential thrombocytosis
Platelets >600*10^9
Blood film: large platelets, megakaryocyte fragments
BM: megakaryocytes + clustering
V617F mutation in 50%
Treatment of essential thrombocytosis - give 4 medications (and some of their downfalls)
- Aspirin (prevent thrombosis)
- Hydroxycarbamide (can worsen anaemia)
- Anagrelide, reduces platelet formation (can transform to MF)
- alpha-IFN useful in <40yos.
Myelofibrosis - what is it characterised by?
2 types?
- Fibrosis of BM + raised megakaryocytes in BM
- Often in older patients
- Also ANAEMIC
Primary = genetic
Secondary = developed from PRV, ET
Major examination finding in myelofibrosis?
MASSIVE Splenomegaly
Blood film in myelofibrosis - 4 features
- Tear drop poikilocytes
- Leukoerythroblasts
- Giant platelets
- Circulating megakaryocytes
Bone marrow in myelofibrosis - 3 things
“Dry tap”
Lots of fibrosis
Megakaryocytes - clustering
Mx of myelofibrosis
Supportive with blood products
- Splenectomy?!
- Hydroxycarbamide (can worsen anaemia)
- Thalidomide
- Steroids
- BMT (experimental)
Prognosis of myelofibrosis? poor prognostic factors?
3-5 years
Severe anemia, thrombocytopenia, massive splenomegaly
CML - sex? age?
Men>F
40-60 years
Typical CML history?
Lethargy/hypermetabolic state (SOB, hyperuricemia, wt loss)/THROMBOTIC EVENT E.G. MONOCULAR BLINDNESS
Typical finding on examination of CML patient? why?
massive splenomegaly - chronic therefore time for cells to accumulate
FBC result on CML
MASSIVE leukocytosis >50 x10^9
Blood film results in CML?
Raised basophils
Raised neutrophil and promyelocytes
<5% BLASTS (if more –> acute leukaemia :( )
Natural, untreated history of CML
- what are the 3 phases?
- Chronic
- Accelerated
- Blast crisis
In what disease phase are 80% of CML patients diagnosed?
chronic
What is the difference between chronic phase and accelerated phase?
Chronic: <5% of cells are blasts
Accelerated: 10-19% are blasts
Key mutation seen in CML and result?
Philadelphia chromosome
t(9;22)
This expresses a fusion gene with TK activity
Most sensitive away to identify leukaemia cells in the body?
RT-qPCR
3 ways to detect leukaemic cells in the body?
FBC - leukocyte levels
Cytogenetic analysis (FISH)
Molecular analysis (RT-qPCR)
3 ways to monitor response to Tx in CML?
FBC
FISH
qPCR
Main drug used for CML treatment? MOA?
Imatinib
a TKI
Survival rate of CML with imatinib treatment?
95% survival at 5 years
Why does imatinib not always work? give 3 reasons
Patient non-compliance
- resistance due to point mutation
- SEs - pleural effusion from fluid retention
