Myeloproliferative disorders

Question 1

Define chronnic myeloid leukaemia?

Answer 1

too many myeloid cells -philadelphia chromosome positive

Question 2

Define: polycythaemia rubra vera/polycythaemia vera

Answer 2

too many red cells

Question 3

Define: essential thrombocythaemia

Answer 3

too many platelets

Question 4

Define: myelofibrosis

Answer 4

excessive fibrosis in the marrow secondary to a probable ET/PRV

Question 5

Of the myeloproliferative neoplasma which ones commonly overlap?

Answer 5

PV, ET and myelofibrosis

Question 6

What do the majority of MPN have?

Answer 6

a genetic abnormality - useful as we can test for them

-if you have a JAK 2 mutation you have either PV, ET or MF

Question 7

What does a mutation in JAK2 cause?

Answer 7

activating tyrosine kinase mutation in pseudokinase domain causes disruption of auto-inhibitory effect on tyrosine kinase activity
=> cell proliferation

Question 8

When is polycythaemia vera more common?

Answer 8

it increases with age but it is not exclusive to the eldelry

Question 9

How does PV present?

Answer 9

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

Question 10

What are the causes of PV?

Answer 10

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

Question 11

What are the aims in treating PV and ET?

Answer 11

Reduce risk of thrombosis and haemorrhage

minimise the risk of transformation to acute leukaemia and myelofibrosis

Question 12

What are the treatments for PV?

Answer 12

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

Question 13

What is the prognosis of PV?

Answer 13

65% survival with treatment and mortality compared with gen pop is 1.6 fold higher
they have increased risk of leukaemia

Question 14

What is the epidemiology of ET?

Answer 14

most common MPN

• 1.5-2/100,000
• Median age 50-55 another peak at 30
• F>M

Question 15

What are the clinical features of ET?

Answer 15

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

Question 16

What are the differential diagnoses for ET?

Answer 16

Cancer
iron deficiency 
acute haemorrhage- infections, inflammatory states 
asplenia 
secondary//reactive

Question 17

How is ET diagnosed?

Answer 17

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

Question 18

What are some independent risk factors of ET?

Answer 18

History thrombosis
age >60

prognosis is essentially the same as normal life as long as it is picked up before catastrophic event

Question 19

What is prefibrotic MF like?

Answer 19

like ET but with dysplastic megakaryocytes +/- early fibrosis - 10 yr survival is pretty good

Question 20

What are the low risks for MF and how is it treated?

Answer 20

age < 60 
platelets <1500
no prior TED/bleeding 
no cardio risks
no hereditary thrombophilia

Tx
- no cytoreductive therapy
+/- ASA

Question 21

What are the intermediate risks for MF and how is it treated?

Answer 21

platelets<1500
age <60
no TED/bleeding 
CVS risk factors 
here thrombophilia

Tx

• reduce CVS risk
• ASA
• reduce platelets in some with cytoreduction

Question 22

What are the high risks for MF and how is it treated?

Answer 22

age >60
platelets>1500
prior TED

Tx

• ASA
• cytoreduction to reduce platelets

Question 23

What is cytoreductive therapy?

Answer 23

used to reduce the risk of hemorrhage

Question 24

What is ASA?

Answer 24

Antithrombotic prophylaxis with aspirin

Question 25

What is the 1st line cytoreductive treatment?

Answer 25

``` hydroxyurea (chemo agent) - ribonucleotide reductase inhibitor - dose 15mg/kg - proven to reduce counts and TED risk SE - Bone marrow suppression - diarrhoea - leukaemogenic? - skin cancer ```

Question 26

What does TED stand for?

Answer 26

thromboembolic disorder

Question 27

What is the 2nd line cytoreductive treatment?

Answer 27

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

Question 28

What treatment for ET is good in young patients or females of child baring age?

Answer 28

low dose pegylated IFNalpha2a | - 30-40% significant decrease in JAK2Mutation allele burden

Question 29

What is the epidemiology of MF?

Answer 29

UK incidence - 0.5-1.5 per 100,000 median age = 60 90% are diagnosed after 40yrs overall median survival is 5 yrs

Question 30

How does MF present?

Answer 30

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

Question 31

What are the main treatments for MF?

Answer 31

``` Blood transfusions AlloSCT if young and fit thalidomide medroxyprogesterone Ruxolitinib - JAK inhibitor ```

Question 32

What are the clinical features of MF?

Answer 32

``` Marrow failure splenomegaly hepatomegaly hypermetabolic syndrome hyperuricaeniia - can get gout from producing lots of uric acid ```

Question 33

What are the diagnostic criteria for MF?

Answer 33

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 ```

Question 34

What investigations should be carried out if you suspect MF?

Answer 34

``` 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 ```

Question 35

What is Ruxolitinib ?

Answer 35

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

Question 36

What is CML?

Answer 36

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

Question 37

What is the genetic basis of CML?

Answer 37

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

Question 38

How does imatinib work?

Answer 38

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

Question 39

Why have newer versions of imatinib needed to be developed?

Answer 39

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

Question 40

What are the main SE of imatinib?

Answer 40

arthralgia | GI upset

Question 41

What are the characteristics of myelodysplasia?

Answer 41

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

Question 42

What are the causes of myelodysplasia?

Answer 42

usually no obvious cause can be secondary to chemotherapy weak familial risk rare inherited bone marrow failure syndromes

Question 43

What factors are important to ask in a hx suspicious of myelodysplasia and what examination findings are likely to be present?

Answer 43

prior exposure to chemotherapy/radiotherapy family hx of MDS/AML dysmorphic features (suggesting congenital bone marrow failure)

Question 44

Where does MDS arise?

Answer 44

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