Hematology Week 3: Myeloproliferative Disorders

Question 1

Myeloproliferative Neoplasm Definition

Answer 1

Question 2

Myeloproliferative Disorders leads to

Answer 2

Question 3

What drives myeloproliferative neoplasm growth?

Answer 3

It is unregulated growth, NOT cytokine-mediated

Question 4

Key types of MPN

3 listed

Answer 4

Polycythemia Vera (PV)

Essential Thrombocythemia (ET)

Primary myelofibrosis (PMF)

Question 5

Polycythemia Vera (PV) Key features

Answer 5

• Overproduction of RBCs

keep in mind MPNs are stem cell disorders so platelets are increased as well but RBC are the prominent form overproduced

Question 6

Essential Thrombocythemia (ET) Key Features

Answer 6

Prominent overproduction of platelets

Question 7

Primary Myelofibrosis (PMF) Key Features

2 listed

Answer 7

• An initial proliferative picture with gradual BM fibrosis
• often see leukocytosis and thrombocytosis early on

Question 8

Key features of MPNs Overview

Answer 8

Question 9

Pathogenesis of MPNs

2 listed

Answer 9

• Tyrosine Kinase Mutations resulting in constitutive activity
• Usually in JAK2 (others are MPL and CALR)

Question 10

JAK2 Point Mutation

Answer 10

JAK2 will be phosphorylated without EPO

Question 11

MPL Receptor mutation

Answer 11

MPL constitutively activated without TPO

Question 12

CALR Mutation

Answer 12

CALR is a highly conserved protein with pleiotropic roles related to its distribution in the endosplasmic reticulum and cytosol, and on the cell surface. In cellular assays, transfection of mutant CALR leads to hyperactivation of the JAK-STAT pathway

Question 13

JAK2 Mutations in MPN

Answer 13

An acquired point mutation in JAK2 (9p) results in a constitutive cytoplasmic tyrosine kinase activity

• growth factor independence
• other proliferative/survival advantages
• V617F phenylalanine substituted for valine

Question 14

JAK2 Mutation Amino Acid change

Answer 14

V617F phenylalanine substituted for valine

Question 15

Acute Myeloid Leukemia Cell types

Answer 15

• Blasts predominate
• Maturation impaired/blocked

Question 16

Chronic Myeloid Leukemia (CML) Cell types

Answer 16

• Neutrophils and other mature cells predominate
• Type of Myeloproliferative neoplasm

Question 17

Polycythemia Vera Cell types

Answer 17

• Mature RBCs, platelets or leukocytes predominate
• myeloproliferative neoplasm

Question 18

Essential Thrombocythemia (ET) Cell Types

Answer 18

• Mature RBCs, platelets or leukocytes predominate
• myeloproliferative neoplasm

Question 19

Myelodysplasia Cell Types

Answer 19

• Mature Cells predominate but are reduced in number in the blood
• Cytopenia(s)

Question 20

MDS/MPN/AML Blood Smears

Answer 20

MDS - cytopenias

MPN - Cytosis

AML - can be cytopenias, cytosis, or normal BUT ALWAYS Neutropenia, severe anemia, severe thrombocytopenia

Question 21

MDS/CML/AML BM Features

Answer 21

MDS

CML

AML - blasts everywhere

MPN - mature cells

Question 22

AML Blood Findings

Answer 22

• Profound cytopenias
• Variable numbers of circulating blasts

Question 23

Myelodysplasia Blood Findings

Answer 23

Cytopenias

always at least one sustained cytopenia (anemia, neutropenia, or thrombocytopenia)

Question 24

Myeloproliferative neoplasms Blood Findings

Answer 24

Elevated cell counts (erythrocytosis, thrombocytosis, leukocytosis (neutrophils, other mature WBCs predominate) (Sustained)

Question 25

1st genetically defined leukemia

Answer 25

CML

Question 26

Always check for?

Answer 26

`BCR-ABL1 for cytosis before JAK2 to rule out CML because great targeted therapy that works

Question 27

MPNs diagnostic criteria

Answer 27

genetic features are key

Question 28

MPNs disorders are characterized by

Answer 28

* uncontrolled cell proliferation (usually multiple lineages) * with intact maturation

Question 29

MPN common hepatosplenomegaly

Question 30

MPNs cheat growth regulation

Answer 30

growth factor independent neoplasms

Question 31

Most common type of MPN

Answer 31

Polycythemia Vera (PV)

Question 32

Polycythemia Vera (PV) Pathogenesis

Answer 32

JAK2 mutation leading to constitutive Tyrosine Kinase activity

Question 33

Polycythemia Vera (PV) Hallmarkl

Answer 33

excess production of mature RBCs but platelets are often increased as well

Question 34

Polycythemia Vera (PV) Disease course

Answer 34

typically indolent but thrombosis or bleeding are significant risk factors

Question 35

Polycythemia Vera (PV) may progress to?

Answer 35

BM Fibrosis

Question 36

Polycythemia Vera (PV) skin changes

Answer 36

Polycythemia rubra vera skin changes

Question 37

Polycythemia Vera (PV) Blood smear

Answer 37

Hgb should of been 13 Hct should be 42-44 Plt should of been ~150,000

Question 38

Polycythemia Vera (PV) BM

Answer 38

her bone marrow is very cellular older patients should have lots of fat these are signs of myeloproliferative neoplasm

Question 39

Other causes of erythrocytosis 3 listed

Answer 39

* Chronic hypoxia - Cardiopulmonary disease is EPO-mediated * EPO-producing neoplasms - Renal cell carcinoma or other tumors that are EPO-mediated * Reduced plasma volume - Hemoconcentration from fluid loss (emesis, dehydration) usually transient **NOT** EPO-Mediated

Question 40

Essential Thrombocythemia (ET) Hallmark

Answer 40

* High platelet count * Thrombocytosis is sustained and is not related to any acute traumatic event * Platelet count might exceed one million/uL (1,000 on CBC)

Question 41

Essential Thrombocythemia (ET) BM findings

Answer 41

Megakaryocytes are markedly increased

Question 42

Essential Thrombocythemia (ET) Pathogenesis

Answer 42

result of JAK2 or (CALR or MPL) mutation resulting in constitutive Tyrosine Kinase activity

Question 43

Essential Thrombocythemia (ET) Disease course

Answer 43

indolent but risk of thrombosis (or rarely bleeding) are significant issues

Question 44

BM of Essential Thrombocythemia (ET)

Answer 44

BM of Essential Thrombocythemia (ET) lots of megakaryocytes and thrombocytosis

Question 45

Primary Myelofibrosis (PMF) Hallmark

Answer 45

begin with leukocytosis, possible thrombocytosis and nucleated RBCs gradually progressive BM failure gradual progressing splenomegaly

Question 46

Primary Myelofibrosis (PMF) physical manifestation

Answer 46

can cause Massive Splenomegaly

Question 47

Primary Myelofibrosis (PMF) BM

Answer 47

Fibrosis in BM

Question 48

Myeloproliferative Neoplasms overview

Answer 48

too much of a good thing

Question 49

Excess RBC production can cause 3 listed

Answer 49

* Plethora/splenomegaly * Sludging * Thrombosis/hemorrhage

Question 50

Excess platelet production 2 listed

Answer 50

* thrombosis/hemorrhage * spontaneous abortions due to thrombosis

Question 51

Excess WBC and platelets production with BM firbrosis can cause 2 listed

Answer 51

* Splenomegaly * Thrombosis

Question 52

Question 1

Answer 52

False

Question 53

Treatment of PV 7 listed

Answer 53

* The goal is to reduce the risk of thrombosis (both venous and arterial) * rarely can become CML * can draw blood (phlebotomy) * Cytoreductive therapy hydroxyurea * interferon * JAK2 inhibitors show promise * Low dose aspirin

Question 54

Treatment of ET 4 listed

Answer 54

Question 55

PV high-risk patients 2 listed

Answer 55

* \>60 yo * history of thrombosis

Question 56

ET high-risk patients 2 listed

Answer 56

* \>60 yo * history of thrombosis

Question 57

Treatment of PMF Anemia 6 listed

Answer 57

* Variable due to variable presentation/symptoms * Often begin with watchful waiting approach * only curative option is HSCT * Anemia * EPO stimulators * Immunomodulatory agents (thalidomide/lenalidomide)

Question 58

Treatment of PMF Splenomegaly

Answer 58

JAK2 inhibitors seem to be really helpful in shrinking spleen size thrombocytopenia is the dose-limiting factor for JAK2 inhibitors

Question 59

Treatment of PMF pharmacology

Answer 59

* EPO can cause thrombosis so have to weigh risk and benefits in a patient with a JAK2 mutation * GCSF can prevent overly neutropenia

Question 60

Risk Stratification of PMF

Answer 60

IPSS - International Prognostic Scoring System