Myeloproliferative disorders Flashcards
Define chronnic myeloid leukaemia?
too many myeloid cells -philadelphia chromosome positive
Define: polycythaemia rubra vera/polycythaemia vera
too many red cells
Define: essential thrombocythaemia
too many platelets
Define: myelofibrosis
excessive fibrosis in the marrow secondary to a probable ET/PRV
Of the myeloproliferative neoplasma which ones commonly overlap?
PV, ET and myelofibrosis
What do the majority of MPN have?
a genetic abnormality - useful as we can test for them
-if you have a JAK 2 mutation you have either PV, ET or MF
What does a mutation in JAK2 cause?
activating tyrosine kinase mutation in pseudokinase domain causes disruption of auto-inhibitory effect on tyrosine kinase activity
=> cell proliferation
When is polycythaemia vera more common?
it increases with age but it is not exclusive to the eldelry
How does PV present?
symptoms:
- headache
- dizziness
- blurred visions dyspnoea- “sluggish blood”
- fill feeling in head
Signs:
- plethora (excessive blood)
- conjunctival suffusion = redness of the conjunctiva that resembles conjunctivitis, but it does not involve inflammatory exudates
- engorged retinal vessels
- tendency to thrombosis - DVT, MI, CVA
- erythromelalgia
- tendency to bleeding - epistaxis, GI bleeding, CVA
Specific:
- acquagenic pruritis = itching with water
- splenomegaly
What are the causes of PV?
Hypoxia = normal physiological response to low oxygen
Smoking = most common cause
Lung disease
Cyanotic heart disease
Altitude
certain rare tumours
rare hb variants - bind O2 too tightly
too much or inappropriate EPO (tumours can produce EPO)
spurious = due to reduced plasma volume, so red cell vol appears increased
What are the aims in treating PV and ET?
Reduce risk of thrombosis and haemorrhage
minimise the risk of transformation to acute leukaemia and myelofibrosis
What are the treatments for PV?
venesection to Hct <0.45 = unit of blood removed anti-platelets if they have too high platelet count = aspirin hydroxycarbamide for thrombocytosis but possibly does increase risk of leukaemic transformation and myelofibrosis
What is the prognosis of PV?
65% survival with treatment and mortality compared with gen pop is 1.6 fold higher
they have increased risk of leukaemia
What is the epidemiology of ET?
most common MPN
- 1.5-2/100,000
- Median age 50-55 another peak at 30
- F>M
What are the clinical features of ET?
Mostly asymptomatic diagnosis Vascular events - thrombosis (arterial >venous) - microvascular occlusive symptoms => erythromelalgia => acroparasthesia => digital ischaemia => neurological = TIA, migraine like headache, dizziness => vision disturbances = transient blindness, blurred vision, photophobia
platelets affect microcirculation = cause pain in hands and feet
What are the differential diagnoses for ET?
Cancer iron deficiency acute haemorrhage- infections, inflammatory states asplenia secondary//reactive
How is ET diagnosed?
diagnostic criteria
- A1-3 or A1 +3-5
A1=sustained platelet count >450
A2= presence of acquired pathogenic mutation
A3= no other myeloid malignancy, esp PV, PMF, CML or MDS
A4= no reactive cause for thrombocytosis and normal iron stores
A5= bone marrow aspirate and trephine biopsy showing increase megakarocyte numbers
What are some independent risk factors of ET?
History thrombosis
age >60
prognosis is essentially the same as normal life as long as it is picked up before catastrophic event
What is prefibrotic MF like?
like ET but with dysplastic megakaryocytes +/- early fibrosis - 10 yr survival is pretty good
What are the low risks for MF and how is it treated?
age < 60 platelets <1500 no prior TED/bleeding no cardio risks no hereditary thrombophilia
Tx
- no cytoreductive therapy
+/- ASA
What are the intermediate risks for MF and how is it treated?
platelets<1500 age <60 no TED/bleeding CVS risk factors here thrombophilia
Tx
- reduce CVS risk
- ASA
- reduce platelets in some with cytoreduction
What are the high risks for MF and how is it treated?
age >60
platelets>1500
prior TED
Tx
- ASA
- cytoreduction to reduce platelets
What is cytoreductive therapy?
used to reduce the risk of hemorrhage
What is ASA?
Antithrombotic prophylaxis with aspirin
What is the 1st line cytoreductive treatment?
hydroxyurea (chemo agent) - ribonucleotide reductase inhibitor - dose 15mg/kg - proven to reduce counts and TED risk SE - Bone marrow suppression - diarrhoea - leukaemogenic? - skin cancer
What does TED stand for?
thromboembolic disorder
What is the 2nd line cytoreductive treatment?
Anagrelide
- inhibits megakarocyte differentiation and platelet aggregation
SE
- fibrosis - needs bone marrow follow up for MF
- haemorrhage with aspirin
- headache, palps, arrhythmia, HF, anaemia
- elderly with heart disease= CAUTION
- 1/3 discontinuation because of SE
What treatment for ET is good in young patients or females of child baring age?
low dose pegylated IFNalpha2a
- 30-40% significant decrease in JAK2Mutation allele burden
What is the epidemiology of MF?
UK incidence - 0.5-1.5 per 100,000
median age = 60
90% are diagnosed after 40yrs
overall median survival is 5 yrs
How does MF present?
fibrotic marrow - bone marrow fails = Hb falls leading to anaemia
cytopenias
very large spleen
hypermetabolic type symptoms
- asymptomatic
- spleen pain
- fevers, sweats, back pain
- infections
often poor prognosis
blood transfusions
What are the main treatments for MF?
Blood transfusions AlloSCT if young and fit thalidomide medroxyprogesterone Ruxolitinib - JAK inhibitor
What are the clinical features of MF?
Marrow failure splenomegaly hepatomegaly hypermetabolic syndrome hyperuricaeniia - can get gout from producing lots of uric acid
What are the diagnostic criteria for MF?
A1 + A2 and any two B criteria
A1= bone marrow fibrosis 3 (0-4 scale)
A2= pathogenetic mutation or absence of both BCR-abl and reactive causes of bone marrow fibrosis
B1 = palpable splenomegaly B2= unexplained anaemia B3= leuco-erythroblastosis B4= Tear drop red cells B5= consitutional symptoms B6= histological evidence of extramedullary haematopoesis
What investigations should be carried out if you suspect MF?
FBC bone marrow aspirate and trephine Molecular test - JAK mutation test (50-60%) - CALR mutation (40%) - Mpl mutation (9%)- more severe phenotype, more transfusion dependent
What is Ruxolitinib ?
oral jak inhibitor = targeted therapy
- rapid improvement in constitutional symptoms
- rapid reduction in splenomegaly
- improvement in blood counts
- transfusion independence
- rapid improvement in QoL
- early data on improved survival
1/3 decrease in spleen vol, decrease in symptoms (anaemia, thrombocytopenia)
Don’t stop it abruptly as it causes ruxolitinib withdrawal syndrome
What is CML?
Type of myeloproliferative disease
- accumulation of myeloid progenitors (proliferation of myeloid cells)
- high white blood cell count
- large spleen
can transform into acute leukaemia
previously treated with myelosuppressive therapy (hydroxycarbamide), transplantation but NOW imatinib
What is the genetic basis of CML?
Philadelphia chromosome
- fusion genes that result in a protein with altered activity
Bcr-abl protein has markedly increased activity - abl gene is involved in cell signalling
How does imatinib work?
revolutionised the treatment for CML
- inhibits the binding of ATP to ABL tyrosine kinase
- more similar drugs are being developed to reduce the SE profile
Why have newer versions of imatinib needed to be developed?
cancers evolve therefore mutations within CML make it resistant to imatinib so next generation BCR-ABL inhibitors have been developed
- nilotinib
- dasatinib
- bosutinib - can cause primary hypertension
- ponatinib
What are the main SE of imatinib?
arthralgia
GI upset
What are the characteristics of myelodysplasia?
disease of the elderly
presents as bone marrow failure - 1 or more of anaemia, neutropenia, thrombocytopenia
chronic myelomonocytic leukaemia has raised monocytes
incidence increases with age
median age is 70
it is not one disease, its a heterogenous clonal disorder of blood cell production - acquisition of a number of heterogeneous changes that sequentially perturb haemopoietic cell fate
What are the causes of myelodysplasia?
usually no obvious cause
can be secondary to chemotherapy
weak familial risk
rare inherited bone marrow failure syndromes
What factors are important to ask in a hx suspicious of myelodysplasia and what examination findings are likely to be present?
prior exposure to chemotherapy/radiotherapy
family hx of MDS/AML
dysmorphic features (suggesting congenital bone marrow failure)
Where does MDS arise?
disorder arises in a haemopoietic stem cells that leads to wonky development manifest by……
- variably reduced numbers of mature red blood cells, white blood cells, platelets
- cells produced are not quite right- look abnormal under microscope and function less well
- primitive cells “blasts” may accumulate as failure to mature normally
cells are less healthy and die quicker
