myeloproliferative neoplasms

Question 1

myeloproliferative neoplasms

Answer 1

clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells
–> in contrast to leukaemia, maturation is relatively preserved

Question 2

types of myeloproliferative disorder

Answer 2

BCR-ABL1 negative
- polycythaemia vera - over production of RBC
- essentrial thrombocythaemia - over pro of platelets
- primary myelofirbosis

BCR-ABL1 positive
- chronic myeloid leukaemia - over production of granulocytes (philadelphia chromosome)

Question 3

when to consider a myeloproliferative neoplasm (MPN)?

Answer 3

No reactive explanation to –
Bloods
 High granulocyte +/-
 High red cell count / Hb +/-
 High platelet count +/-
 Eosinophilia/basophilia

o Splenomegaly
o Thrombosis in an unusual place

Question 4

features commone to MPN

Answer 4

asymptomatic
increased cell turnover - gout, fatigue, weaight loss, sweats
splenomegaly symptoms
marrow failure

thrombosis - arterial or venous, TIA, MI, claudication

Question 5

chronic myeloid leukaemia

Answer 5

cytogenic change = Philadelphia chromosome t(9;22) translocation

proliferation of myeloid cells - granulocytes + their precursors, other lineages (platelets)

fatal without stem cell/bone marrow transplantation in chronic phase

Question 6

genetics of chronic myeloid leukaemia

Answer 6

philadelphia chromosome results in a new (chimaeric) gene) -> BCR-ABL1

gene product is a tyrosine kinase which causes abnormal phosphorylation ( signalling) leading to the haematological changes in CML

–> durable disease responses with tyrosine kinase inhibitors

Question 7

phases of chronic myeloid leukaemia

Answer 7

1. chronic phase – can last around 5yrs, often asymptomatic, accidental diagnosis with raised WCC
2. accelerated phase –
   a. abnormal blast cells take up a high proportion of cells in bone marrow + blood
   b. patients become more symptomatic – anemia, thrombocytopenia, immunocompromised
3. blast phase
   a. even high proportion of blast cells + blood
   b. severe symptoms + pancytopenia – often fatal

Question 8

chronic myeloid leukaemia

Answer 8

asymptomatic
splenomegaly
hypermetabolic - weight loss, weating
gout
priapism - prolonged erection

Question 9

blood count findings in chronic myeloid leukaemia

Answer 9

normal/low Hb
leucocytosis with neutrophilia + myeloid precursors (myelocytes), eosinophilia, basophilia

-> an increase in granulocytes at different stages of maturation +/- thrombocytosis

Question 10

management of chronic myeloid leukaemia

Answer 10

imatinib
- inhibitor of tyrosine kinase assoc with BCR-ABL defect

(CML is the paradigm for targeted therapies in oncology)

Question 11

polycythaemia vera

Answer 11

myeloproliferative disorder caused by clonal proliferation of marrow stem cell leading to an increase in red cell volume
- often accompanied by overproduction of neutrophils + platelets

high Hb/haemocrit accompanied by erythrocytosis

JAK2 present in 95%
peak incidence = 60s

Question 12

different types of polycythaemia vera

Answer 12

primary = polycythaemia vera

secondary polycythaemia -> chronic hypoxia, smoking, erythropoietin-secreting tumour

pseudopolycythaemia (relative) -> dehydration, diuretic therapy, obesity

Question 13

how to distinguish between true vs pseudo polycythaemia

Answer 13

red cell mass studies

in true -> total red cell mass >35ml/kg in males + >32ml/kg in females

Question 14

polycythaemia vera presentation

Answer 14

MPN features
headache, fatigue
increased BLOOD viscosity - arterial/venous thrombosis
haemorrhage - secondary to abnormal platelet function

aquagenic puritis (itch after a hot bath)

Question 15

polycythaemia vera investigation

Answer 15

FBC + Flm
- raised haemocrit, neutrophils, basophils, platelets (raised in half)
- low esr
- raised leukocyte alkaline phosphatase

JAK2 mutation status - mutational analysis

investigate for secondry/pseudo causes
- CXR, O2 sats, arterial blood gases, drug history

Question 16

JAK2 mutation

Answer 16

JAK2 = a kinase
mutation (substitution) results in a loss of auto-inhibittion
- activation of erythropoiesis in the absence of ligand

mutations present in >95% of polycythaemia vera patients
- *mutational analysis froms part of intital screening + has replaced a number of other tests

Question 17

management of polycythaemia vera

Answer 17

venesect to haemocrity <0.45
aspirin (reduces thrombosis)
hydroxycarbamide (cytotoxic oral chemo)

5-15% progress to myelofibrosis or acute leukaemia (risk increased with chemo treatment
*thrombotic event = significant cause of morbidity + mortality

Question 18

essential thrombocythaemia/thrombocytosis (ET)

Answer 18

uncontrolled over production of abnormal platlets

abnormal platelet function leads to
- thrombosis
- at high levels can also cause bleeding due to acquired von Willebrand disease

Question 19

essential thrombocytosis presentation

Answer 19

MPN futures - esp vaso-occlusive complications
both thrombosis (venous+arterial) + haemorrage

burning sensation in hands
unpredictable bleeding risk, esp at surgery

platelet count >600 x109/l

Question 20

diagnosis of ET

Answer 20

exclude reactive throbocytosis - blood loss, inflammation, malignancy, iron deficiency
exclude CML

genetics
- JAK2 in 50-60%
- CALR (calreticulin) in 25%
- MPL in 5%
- 10-20% will be “triple negative”

characteristic bone marrow appearances

Question 21

management of essential thrombocytosis

Answer 21

antiplatelet agents
cytoreductive therapy to control proliferation
- hydroxycarbamide (hydroxyurea)
- anagrelide
- interferon alpha

Question 22

causes of thrombocytosis

Answer 22

reactive - infection, surgery, iron deficiency anaemia

malignancy
essential thrombocytosis or other myeloproliferative disorder
hyposplenism

Question 23

myelofibrosis

Answer 23

thought to be caused by hyperplasia of abnormal megakaryocytes
- resultant release of platelet derived growth factor is though to stimulate fibroblasts

haematopoiesis develops in liver + spleen (extramedullary)

can be idiopathic or post polycythaemia or essential thrombocythaemia

Question 24

myelofibrosis presentation

Answer 24

marrow failure - anemia, bleeding, infection
massive splenomegaly
- LUQ abdo pain, draggin sensation
- complications - portal hypertension

hyercatabolism - weight loss, night sweats
MPN features

Question 25

myelofibrosis investigation

Answer 25

blood film
- *tear drop shaped RBC
- leucoerythroblastic

dry aspirate
fibrosis on trephine biopsy

JAK2, CALR, MPL mutations - 10% triple neg

Question 26

myelofibrosis management

Answer 26

supportive care
- blood transfusion
- platelets
- antibiotics

allogenic stem cell transplantatio in a select few
splenectomy - CONTROVERSIAL

JAK2 inhibitors - improve spleen size, constitutional symptoms

Question 27

reactive causes of inreased granulocytes

Answer 27

infection - pyogenic bacteria causing neutrophilia

physiological - post surgery, steroids

Question 28

leucoerythroblastic film

Answer 28

presence of granulocyte left shift (immature) as well as nucleated red blood cells on the same blood film
-> this is always an abnormal finding, and may indicate a major acute stress or bone marrow infiltration.

causes
- Acute stress - haemorrhage, shock
- Bone marrow infiltration - myeloproliferative neoplasms, leukaemias, lymphomas, myeloma, metastatic cancer
- G-CSF administration