40 - Chronic Myeloid Proliferative disease

Question 1

Chronic myeloproliferative disorder definition

Answer 1

Clonal stem cell disorders of the bone marrow

Malignant

Question 2

E.gs of CMPD

Answer 2

Polycythaemia vera
Essential thrombocytosis
Idiopathic myelofibrosis

Question 3

Polycythaemia vera

Answer 3

Increased RBCs
±neutrophils
±platelets
Need to distinguish between 2° polycythaemias and relative polycythaemias

Question 4

Essential thrombocythaemia

Answer 4

Increased platelets

Need to distinguish from reactive thrombocytosis

Question 5

Myelofibrosis

Answer 5

Variable cytopenias with a large spleen

Need to distinguish from other causes of spinomegaly

Question 6

Polycythaemia vera - age distribution

Answer 6

All ages

Peak at 50-70

Question 7

Polycythaemia vera - symptoms

Answer 7

Insidious 
Itching (aquagenic - hot baths)
Plethoric face
Headache, muzziness, general malaise
Tinnitus 
Peptic ulcer
Gout
Gangrene of the toes

Question 8

Polycythaemia vera - signs

Answer 8

Plethora
Engorged retinal veins
Splenomegaly

Question 9

Polycythaemia vera - diagnosis

Answer 9

Persistent increased Hb/hct >0.5

Distinguish: relative vs absolute polycythaemia
&
primary vs secondary polycythaemia

Question 10

Primary polycythaemia =

Answer 10

Polycythaemia vera

Question 11

2° polycythaemia causes

Answer 11

Central hypoxic processes inc. chronic lung diseases, R->L shunts heart disease, CO poisoning, smoker, high altitude

Renal disease
EPO production tumours
Drugs: androgen preparations, postrenal transplant erythrocytosis

Congenital: high O2-affinity Hb; EPO receptor mediated

Idiopathic

Question 12

Polycythaemia vera - second line tests

Answer 12

If EPO elevated: CXR, ABG, USS abdomen

EPO normal or low: JAK2 mutation, bone marrow exam, EXON12 mutation

Question 13

JAK

Answer 13

Janus kinases (tyrosine kinases)

Signalling pathway for cytokine receptors

Presence of JAK2 V617F mutation in peripheral blood DNA is diagnostic for myeloproliferative disorders

Question 14

JAK test

Answer 14

Allele specific DNA-based PCR

Question 15

Polycythaemia vera - treatment

Answer 15

Venesections aim HCT

Question 16

Thrombocytosis - two types

Answer 16

Primary
Reactive - surgery, infection, inflammation, malignancy, Fe deficiency, hyposplenism, haemolysis, drug induced, rebound post chemo

Question 17

Thrombocytosis - investigation

Answer 17

Persistent platelets >450 x109/l

1st line: FBC and film, ferratin, CRP, CXR, ESR

Question 18

Thrombocytosis - 2nd line investigations

Answer 18

JAK2
CALR
Bone marrow biopsy
Extensive search for 2° cause

Question 19

CALR mutation

Answer 19

Calreticulin mutation

Cell signalling protein produced in ER
Mutation of Exon 9
Found in myeloid progenitors in ET
Mechanism of action unknown 
Found in up to 90% of JAK2 negative ET

Question 20

Thrombocytosis - diagnosis

Answer 20

JAK2 - 50%

CALR mutation - 45%

Question 21

Thrombocytosis - treatment

Answer 21

Assess thrombotic risk - age, hypertension, diabetes, platelet count >1500, history of thrombosis

Antiplatelet treatment - aspirin 75mg daily, cytoreduction is high risk

Question 22

How do you do cytoreduction?

Answer 22

Hydroxycarbamide
Inferferon
Anagrelide
P32

Question 23

Thrombocytosis - prognosis

Answer 23

Excellent - 20 yr median survival

Risk of AML or myelofibrosis

CALD mutated have lower thrombosis risk

Question 24

Myelofibrosis - presentation

Answer 24

Pancytopenia
B symptoms
Massive splenomegaly

Question 25

Myelofibrosis - investigations

Answer 25

FBC and film | Haematinics

Question 26

Myelofibrosis - diagnosis

Answer 26

Blood film Bone marrow results JAK2 mutation (50%) CALR mutation (30%)

Question 27

Splenomegaly - causes

Answer 27

CHICAGO ``` Cancer Haematological Infection Congestion Autoimmune Glycogen storage disorders Other - amyloid ```

Question 28

Myelofibrosis - treatment

Answer 28

Supportive care JAK2 inhibitors Bone marrow transplant

Question 29

Myelofibrosis - prognosis

Answer 29

Poor - median survival 5 years

Question 30

Chronic myeloid leukaemia - prevalence

Answer 30

Rare 1 per 100,000 Median age is 55-60 M:F = 1.5:1

Question 31

Chronic myeloid leukaemia - characteristics

Answer 31

Leucocytosis+++ Leucoerythroblastic blood picture Anaemia Splenomegaly

Question 32

Chronic myeloid leukaemia - symptoms

Answer 32

``` Ab discomfort Ab pain Fatigue Venous occlusion Gout ```

Question 33

Chronic myeloid leukaemia - treatment for chronic phase

Answer 33

Low dose oral cytotoxic drugs (busulphan, hydroxycarbamide, IFN)

Question 34

Chronic myeloid leukaemia - treatment for acute crisis

Answer 34

Intensive chemo | Poor outcome

Question 35

Chronic myeloid leukaemia - allogenic bone marrow transplant

Answer 35

Curative in 50% of patients

Question 36

Chronic myeloid leukaemia - imatinib resistance

Answer 36

Activating loop mutations in BCR-ABL confer resistance and loss of disease control New TKI e.g. nilotinib, dasatinib

Question 37

Chronic myeloid leukaemia - imatinib use

Answer 37

Designer molecular therapy Model and paradigm for other cancers Tyrosine kinase inhibitors (TKIs) increasingly used in solid tumours

Question 38

Chronic myeloid leukaemia - summary

Answer 38

Pluripotent stem cell disorder Defined by the t(9;22) translocation Driven by BCR-ABL fusion tyrosine kinase Chronic phase followed by acute transformation Designer molecule treatment (imatinib) has proved highly successful BCR-ABL mutations confer resistance to imatinib