Haematology 10: CML and myeloproliferative disorders

Question 1

What are MPNs?

Answer 1

Myeloproliferative neoplasms:

A myeloproliferative disorder that lead to an excess of differentiated myeloid cells (platelets, RBCs and leukocytes)

Question 2

What are some examples of MPNs? mutation / what proportion?

Answer 2

Essential Thrombocythaemia - JAK2 (55%)

Polycythaemia Vera - JAK2 (95%)

Myelofibrosis - JAK2 (50%)

CML (classesd as an MPN)

Question 3

What is essential thrombocythaemia? cause?

Answer 3

Megakaryocytes are making too many platelets leads to a v. high platelet count (>450 consistently)

JAK2 mutation in 55%

No evidence of other cause

Question 4

What is the mx of essential thrombocythaemia?

Answer 4

Aspirin to reduce stroke risk

Hydroxycarbamide to lower count

Question 5

What is polycythaemia (ruba) vera

Answer 5

Excess RBC production -> Haematocrit >0.52 / 0.48 (M / F), Often thrombocythaemia as well

Hyperviscosity, hypervolaemia, hypermetabolism -> Headaches, light-headedness, visual disturbance, fatigue, dyspnoea

High risk of thrombotic events e.g. MI, Stroke, Budd-Chiari (portal vein thrombosis)

95% association w/ JAK2

Question 6

What is the mx of polycythaemia vera?

Answer 6

Aspirin to reduce stroke risk

Venesection (taking blood to lower haematocrit)

Hydroxycarbamide to lower count

Question 7

How does myelofibrosis occur?

Answer 7

Clonal proliferation of stem cells in the bone marrow

This results in cytokine release and fibrosis of the bone marrow

As a result, there is reduced production of all cell lineages (this is different to the other ones as they have increased production)

NB: Polycythaemia vera and essential thrombocythaemia can both progress to this

Question 8

What are the features of myelofibrosis?

Answer 8

JAK2 mutation present in 50%

Pancytopenia

Splenomegaly (can be massive splenomegaly) - as seen in Exam Qs

Question 9

What else can classically present with massive splenomegaly in exam Qs?

Answer 9

CML
Myelofibrosis
Leishmanasis

Question 10

Mx of myelofibrosis?

Answer 10

Stem cell transplant likely only cure - if early and before BM has fibrosed

Ruloxitnib - JAK inhibitor

Question 11

What are the different types of polycythaemia vera?

Answer 11

Primary - familial / PV

Secondary - Disease, high altitude, chronic hypoxia

Pseudo - reduced plasma volume, dehydration

Question 12

Difference between early and late myelofibrosis?

Answer 12

Prefibrotic -> mild changes, isolated thrombocytosis

Fibrotic -> splenomegaly, blood changes, dry tap (BUZZWORD), prominent collagen fibrosis in histological section, osteoscleoris

Question 13

Typical presentation of CML?

Answer 13

• Typically onset age 35-55 in EMQs
• LUQ pain - Splenomegaly
• Mostly asymptomatic if diagnosed in chronic phase

May present with symptoms of acute leukaemia if in accelerated / blast phase (~10%) - not seen as much these days

Question 14

CML blood test results?

Answer 14

WCC - V. high (can include all different stages - myelocytes to neutrophils)
Hb normal or low
Plt - high initially but can drop later in disease

Basophils - Raised (caused by few conditions)
Monocytes - Should be low (if its high indicates CMML)

Question 15

Blood film of CML?

Answer 15

• “Left shift”
• Leukocytosis
• Eosinophilia
• Basophilia

Hypoloblated megakaryocytes

Question 16

What is the genetic cause of CML and how is this detected?

Answer 16

Nearly all CML is associated w/ philadelphia chromosome

BCR-ABL1 fusion gene due to t(9;22) and formation of Philadelphia chromosome

This is detected by FISH (Fluorescence in situ hybridization) studies

Question 17

What are the different phases of CML?

Answer 17

Chronic (85-90%)

Accelerated (median 6-12m):
Increasing number of blasts in BM (>10%)
Lack of response to therapy
Additional abnormalities in addition to BCR-ABL1

Blast crisis (median survival 3-6m):
>20% blasts in bone marrow (FLAWS for months)
Behaves like an acute leukaemia

Question 18

How to differ between CML in blast crisis v AML?

Answer 18

Ph Chr BCR-ABL present in all CML

Hx of CML

CML neutrophilia + L shift + basophilia

Question 19

What is the Mx of CML? prognosis?

Answer 19

Tyrosine Kinase Inhibitors
1st Generation: Imatinib (MAIN ONE)
2nd Generation: Dasatinib, Nilotinib, Bosutinib
3rd Generation: Ponatinib

> 90% 10y survival -> Small percentage of patients will fail treatment and need transplants

Question 20

Which of the following mutations is diagnostic for polycythaemia rubra vera?

Calreticulin
JAK2 V617F
MPL
CFTR F508
TP53

Answer 20

JAK2 V617F

Question 21

Which of the following is used to manage CML?

Ibrutinib
Imatinib
ABVD
Brentuximab vedotin
CAR-T cell therapy

Answer 21

Imatinib - (BCR-ABL) Tyrosine Kinase inhibitor

Question 22

Which of the following translocations is responsible for the Philadelphia chromosome?

t(15;17)
t(8;14)
t(11;14)
t(14;18)
t(9;22)

Answer 22

E - t(9;22) = CML

A: PML-RARA fusion oncogene in acute promyelocytic leukaemia (APML); aggressive form a/w DIC; rx ATRA
B: c-Myc oncogene
C: cyclin D1 (mantle cell)
D: bcl-2 (follicular)

Question 23

What MPN might show dry tap (inc reticulin / collagen fibrosis) on BM?

Answer 23

Myelofibrosis

Question 24

What MPN might show teardrop poikilocytes and leukrythroblasts and giant plts?

Answer 24

Myelofibrosis