Myeloproliferative Disorders Flashcards
Which mutations are commonly associated with myeloproliferative disorders?
Why is it important to look genetic mutations for these disorders?
JAK2 = 97% of mutations in polycythemia
CALR
MPL
Can identify and diagnose MPN due to them having a defined genetic abnormality
Which cells are in excess in each of these myeloproliferative neoplasms?
CML
PV (polycythaemia Vera)
ET (essential thrombocythaemia)
MF (myelofibrosis)
CML= myeloid cells PV= red cells ET= platelets MF= excessive fibrosis
What is the classic presentation + FBC of polycythaemia?
Why are these people at an increased risk of clot formation?
Middle aged man DVT in calf Pruritus (itchy skin) after hot bath Plethoric (red face) Palpable spleen (splenomegaly)
FBC:
Hb= 20.4 ie very high
Leads to increased blood viscosity so increased risk of clot formation
What are the symptoms of PV and what is the major underlying cause?
What are the signs associated with PV?
Symptoms : Headache Dizziness Blurred vision “Full” feeling head All due to increase blood viscosity
Signs:
Plethora
Conjunctival suffusion (reddening of conjunctiva w/o inflammatory cause)
Engorged retinal vessels
Increased thrombosis tendency (DVT, MI, CVA)
Erythromelalgia (burning pain and redness in feet and hands etc)
Increased bleeding tendency
Hypertension
Acquagenic pruritis= itching after contact with water
Splenomegaly
What are the causes of PV?
JAK2 mutation= present in 95% of patients
Hypoxia - increasing number of RBC is the normal response to low oxygen environment
I.e. smoking/lung disease/cyanotic heart disease/altitude
Rare tumours
Rare Hb variants
Excess or inappropriate erythropoietin
What are the main aims of treatment for PV?
Decrease the risk of thrombosis and haemorrhage
Minimise the risk of transformation to acute leukaemia and myelofibrosis
What are the treatment options for PV? Give their role or indications.
Venesection (removing blood)= acts to decrease the haematocrit to below 0.45
Anti-platelets (75mg Asparin)
Hydroxycarbamide (weak chemo) = used when platelet count also raised because removing blood would not lower platelets
I.e. has thrombolysis action to combat thrombocytosis
What are the clinical features associated with essential thrombocythaemia? What is the cause of a significant number of these symptoms?
Asymptomatic (applies to most at diagnosis)
Thrombosis
Symptoms caused by microvascular occlusion:
Erythromelalgia
Acroparasthaesia (pins and needles in hands and feet)
Digital ischaemia
TIA
Migraine-like headache
Dizziness
Visual disturbances
Paradoxical bleeding= excess platelets impairs coagulation (platelets >1500)
How can essential thrombocythaemia be diagnosed?
Most important= characterising the genetic abnormality i.e. JAK2/MPL/CALR
No other explanation for symptoms i.e. other myeloid malignancy or reactive thrombocytosis
Platelet count sustained above 450 x 10 power 9/L
What are differential diagnosis for thrombocytosis seen in ET (i.e. raised platelets) ?
Secondary/reactive Cancer Iron deficiency Acute haemorrhage Infections Inflammatory state Asplenia
What is the criteria for a low risk ET patient? How does this correlate to the treatment they receive?
<60 yo Platelets <1500 No prior TED or bleeding No CVS risk No hereditary cytopenia
TX:
No cytoreductive therapy
Watch and weight (W+W)
Potential for low dose aspirin
What is the criteria for a intermediate risk ET patient? How does this correlate to the treatment they receive?
Platelets<1500 Age<60 No TED (thromboembolic disease) CVS risk factors Hereditary thrombophilia
TX:
Decrease CVS risk
ASA (Asparin)
Decrease platelets with cytoreduction
What is the criteria for a high risk ET patient? How does this correlate to the treatment they receive?
Age>60
Platelets>1500
Prior TED
TX:
ASA
Cytoreduction to decrease platelets
What is cytoreductive therapy?
Cytoreductive= used to reduce the risk of haemorrhage in patients with high platelet counts in ET
What is the mechanism of hydroxyurea? What are the associated SE?
Ribonucleatide reductase inhibitor = 1st line cytoreductive tx
SE: BM suppression Diarrhoea Leukaemogenic Skin cancer Possible teratogen
What is the mechanism of anagrelide? What are the associated SE?
Inhibits megakaryocyte differentiation and platelet aggregation
SE: Fibrosis Haemorrhage on aspirin Headaches Palpitations Arrhythmias Fluid retention HF Anaemia
What is an alternative cytoreductive drug for hydroxyurea? Why is this drug sometimes used instead?
Low dose pegylated IFN alpha 2a
Hydroxyurea is classed as mild chemo which means it carries the associated risk factors and possible carcinogenic effects
What is myelofibrosis?
Fibrotic marrow formed due to scarring from MPN i.e. PV or ET
How does myelofibrosis present?
Splenomegaly Hepatomegaly Cytopenia Spleen pain Fever + sweats Back pain Infections Weight loss = hypermetabolic symptom Hyperuricaemia = elevated uric acid levels
How can you treat myelofibrosis?
Blood transfusion AlloSCT (allogenic stem cell transplant) Thalidomide Medroxyprogesterone Ruxolitinib (JAK inhibitor)
What are the benefits of using Ruxolitinib to treat myelofibrosis? What is ruxolitinib withdrawl syndrome?
Decreased constitutional symptoms Decreased splenomegaly Increased survival benefit Improved FBC Increased QOL Transfusion independent- benefit if px not suitable for transplant
Occurs when treatment stopped too abruptly
How is myelofibrosis diagnosed?
How would you describe a blood film from MF and what would you expect to see?
Bone marrow aspiration and trephine to identify bone fibrosis
FBC
Molecular test to identify mutations (JAK2/CALR/MPL)
Leucoerythroblastic i.e. in conditions where bone is rapidly/constantly being replaced
Cells:
- nucleated red cell
- myelocyte
- tear drop RBC
What is CML and what causes it?
Accumulation of myeloid progenitors due to Philadelphia chromosome i.e. BCR-ABL fusion= increased cell signalling to drive myeloid proliferation
How can CML be treated? How do patients respond to the TX?
What are the potential problems with this TX?
Imatinib= inhibits ATP binding to ABL tyrosine kinase to prevent action of BCR-ABL fusion protein
Normal platelet and WC count
Decrease in Philadelphia chromosome number i.e. return to normal cytogenetic
Molecularly normal
Therefore= “cures” patients and leads to progression free survival
Resistance
Alternatives used
