83 Polycythemia Vera

Question 1

The term denoting an increased amount of blood cells that has traditionally been applied to conditions in which the mass of erythrocytes is increased

Answer 1

Polycythemia

Question 2

TRUE OR FALSE

In polycythemia vera, there is more than one cell lineage increased at diagnosis and through the course of the untreated disease, from erythrocytosis, an invariably unilineage increase in red cells

Answer 2

TRUE

In polycythemia vera, there is more than one cell lineage increased at diagnosis and through the course of the untreated disease, from erythrocytosis, an invariably unilineage increase in red cells

Question 3

A characteristic feature of PV on BMA

Answer 3

Endogenous erythroid colonies (EECs)

Erythropoietin-independent BFU-E precursors

Question 4

A situation wherein a part of a chromosome comes in two copies from one parent and no copy from the other parent.

Answer 4

Uniparental disomy (UPD)

In PV, UPD is the acquired somatic event generated by mitotic crossover, wherein one part of the chromosome is duplicated and the other is deleted as it happens in at least part of the PV clone.

Question 5

JAK2 V617F is located at what chromosome

Answer 5

Chromosome 9p

Question 6

The V617F mutation is present in:

PV:
ET and PMF:

Answer 6

PV: All
ET and PMF: more than 50%

Question 7

In PV (unlike in ET), it is often in its associated (homozygous or heterozygous) form as a result of UPD, at least in some of the progenitors

Answer 7

In PV (unlike in ET), it is often in its associated HOMOZYGOUS form as a result of UPD, at least in some of the progenitors

Question 8

Patients bearing homozygous JAK2 V617F tend to have:

Answer 8

Longer duration of disease
Higher hemoglobin levels
Increased incidence of pruritus
More likely to transform to post-polycythemia vera MF (post-PV MF)
Increased spleen volume
Increased leukocytosis
Increased severity of MF

Question 9

Kind of JAK2 mutation is present in PV patients who are JAK2 V617F -negative

Answer 9

JAK2 exon 12 mutations

Question 10

Patients with JAK2 exon 12 mutations have:

Answer 10

Erythrocytosis only
Occurs at a younger age
Higher hemoglobin
Normal EPO level
Differences in marrow morphology- megakaryocytic clusters are largely absent and lack of panmyelosis

Disease course and clinical outcome, however, are similar.

Question 11

Mutation in patients with polycythemia with eosinophilia which has no evidence of uniparental disomy and all erythropoietin-independent BFU-E were heterozygous for this novel JAK2 mutant.

Answer 11

JAK2 exon 13

Question 12

The risk of acquiring a JAK2 V617F -positive MPN is three- to fourfold higher in patients with the_________________haplotype.

Answer 12

JAK2 GGCC (46/1) haplotype

Question 13

Could be considered be the “fourth” driver mutation in Philadelphia chromosome negative MPNs, in addition to JAK2, CALR and cMPL

Answer 13

LNK protein mutations (encoded by SH2B3 gene)

Question 14

A history of any autoimmune disorder has been associated with a _____ increased risk of developing an MPN

Answer 14

20%

Question 15

PV usually has an insidious onset, most commonly during the _________ decade of life, although onset may occur from childhood to old age.

Answer 15

Sixth decade of life

Question 16

TRUE OR FALSE

Other PV patients may be uncovered during investigation for arterial or venous thrombosis, or iron deficiency.

Answer 16

TRUE

Other PV patients may be uncovered during investigation for arterial or venous thrombosis, or iron deficiency.

Question 17

The most common symptoms of PV

Answer 17

Headache

In decreasing order of frequency: headache, fatigue, weakness, pruritus, dizziness, and night sweats, but these symptoms are more likely in patients with PV transforming to MF

Question 18

The most common and most important complication of PV

Answer 18

Thrombotic episodes

Question 19

Thrombotic episodes occur in about _________ of PV patients

Answer 19

One-third

Question 20

The most common serious complication of PV

Answer 20

Cerebrovascular accident

Question 21

Bleeding and bruising is a common complication of PV, occurring in approximately __________of patients in some series.

Answer 21

One-quarter

Question 22

TRUE OR FALSE

Bleeding is more common in persons with marked thrombocytopenia

Answer 22

FALSE

Bleeding is more common in persons with marked thrombocytosis (>1000 × 10 9 /L).

Question 23

Syndrome caused by a thrombosis in the hepatic venous outflow, leading to ischemia from reduced perfusion through hepatic arterioles and necrosis of hepatocytes

Answer 23

Budd-Chiari syndrome

Budd-Chiari syndrome may be the first clinical manifestation of PV

Question 24

TRUE OR FALSE

PV is the most frequent underlying disease associated with Budd-Chiari syndrome.

Answer 24

TRUE

PV is the most frequent underlying disease associated with Budd-Chiari syndrome.

Question 25

Treatment for Budd-Chiari syndrome

Answer 25

Transjugular intrahepatic portosystemic shunt placement Liver transplantation

Question 26

Cause of aquagenic pruritus in PV patients

Answer 26

Increased numbers of mast cells in the skin and elevated histamine levels

Question 27

Syndrome characterized by warmth of the extremities; painful, reddened digits; a burning sensation; and erythema of the fingers, hands, and feet that is associated with **thrombocytosis**.

Answer 27

Erythromelalgia ## Footnote * A causative role for transient microvascular occlusion by platelet aggregates has been proposed * It is not specific to PV or other MPNs

Question 28

Treatment for erythromelalgia

Answer 28

Low-dose aspirin

Question 29

# TRUE OR FALSE It is advised to normalize blood counts and blood volume before surgical interventions, and use specific preventive measures preoperatively.

Answer 29

TRUE It is advised to normalize blood counts and blood volume before surgical interventions, and use specific preventive measures preoperatively.

Question 30

Phase of PV characterized by a combination of **anemia (non–iron deficiency), progressive increase of splenic size**, and in most, but not all instances, represents **post-PV MF**

Answer 30

Spent phase of PV ## Footnote * First noticed when phlebotomy requirements decrease * The appearance of significant anisocytosis and poikilocytosis and teardrop cells (dacryocytes) heralds the onset of the spent phase and postPV MF * Associated with an increased risk of leukemic transformation

Question 31

In the updated 2016 WHO diagnostic criteria for PV, the hemoglobin level must be: Male: Female:

Answer 31

Male:16.5 g/dL Female: 16.0 g/dL

Question 32

# TRUE OR FALSE In patients treated with HU, MCV decreases to very low values

Answer 32

FALSE In patients treated with HU, **MCV increases** to very high values

Question 33

# TRUE OR FALSE Red cell mass determination is not useful in distinguishing PV from secondary erythrocytosis because the red cell mass is increased in both disorders.

Answer 33

TRUE Red cell mass determination is **not useful in distinguishing PV from secondary erythrocytosis** because the red cell mass is increased in both disorders.

Question 34

The principal value of red cell mass determination is to

Answer 34

Distinguish PV from apparent or spurious erythrocytosis Distinguishing cases of masked PV from ET

Question 35

Absolute neutrophilia occurs in about __________ of patients with PV.

Answer 35

Two-thirds ## Footnote Neutrophils may be an important factor in PV-associated thrombosis.

Question 36

Basophilia occurs in approximately _____________of patients with uncontrolled disease.

Answer 36

Two-thirds

Question 37

The platelet count is increased in approximately_______ of patients with PV at the time of diagnosis, and in approximately ______of patients it is greater than 1000 × 10 9 /L

Answer 37

50% has increased platelet count 10% of patients it is greater than 1000 × 10 9 /L

Question 38

# TRUE OR FALSE There are no consistent abnormalities of thrombopoietin levels in patients with PV.

Answer 38

TRUE There are no consistent abnormalities of thrombopoietin levels in patients with PV.

Question 39

# TRUE OR FALSE Patients with MPNs often display a nearly pathognomonic defect in the primary wave of platelet aggregation induced by epinephrine

Answer 39

TRUE Patients with MPNs often display a nearly pathognomonic **defect in the primary wave of platelet aggregation induced by epinephrine**

Question 40

Platelet counts over 1000 × 10 9 /L are associated with

Answer 40

Acquired, type 2 von Willebrand disease ## Footnote Increased risk of bleeding, but not of thrombosis

Question 41

Plasma levels of Vitamin B12 and Uric Acid are (increased or decreased)

Answer 41

INCREASED

Question 42

# TRUE OR FALSE Plasma has been used for detection of the JAK2 V617F DNA and mRNA mutation and zygosity state, plasma analysis is reliable.

Answer 42

FALSE Plasma has been used for detection of the JAK2 V617F DNA and mRNA mutation and zygosity state, but plasma analysis is not reliable.

Question 43

# TRUE OR FALSE JAK2 exon 12 mutations are found in ET.

Answer 43

FALSE JAK2 exon 12 mutations are **not found in ET.**

Question 44

Serum erythropoietin levels in patients with PV is (below or above) the normal reference range.

Answer 44

Below the normal reference range

Question 45

# TRUE OR FALSE An elevated erythropoietin level generally excludes the diagnosis of PV, but a normal or even increased erythropoietin levels can be seen in Budd-Chiari syndrome; normal erythropoietin is more likely to be encountered in PV subjects with JAK2 exon 12 mutations.

Answer 45

TRUE An elevated erythropoietin level generally excludes the diagnosis of PV, but a normal or even increased erythropoietin levels can be seen in Budd-Chiari syndrome; normal erythropoietin is more likely to be encountered in PV subjects with JAK2 exon 12 mutations.

Question 46

The most specific and sesitive test for PV

Answer 46

Detection of EECs in cultures of blood or marrow

Question 47

In terms of EECs, difference between PV vs PFCP and congenital disorders of hypoxia sensing

Answer 47

EECs in PFCP and congenital disorders of hypoxia sensing, are abrogated by pretreatment with erythropoietin and erythropoietin receptor-blocking antibodies

Question 48

# TRUE OR FALSE Absent or decreased iron stores are seen in the marrow of many patients with PV.

Answer 48

TRUE Absent or decreased iron stores are seen in the marrow of many patients with PV.

Question 49

World Health Organization Criteria for The Diagnosis of Polycythemia Vera, 2016

Answer 49

Major Criteria 1. Hemoglobin >16.5 g/dL (men), >16.0 g/dL (women) OR Hematocrit >49% (men), >48% (women) OR Increased red cell mass >25% above mean predicted value 2. Bone marrow biopsy showing hypercellular for age, trilineage myeloproliferation (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes (differences in size) 3. Presence of JAK2V617F or JAK2 exon 12 mutation Minor Criterion 1. Subnormal serum erythropoietin level ## Footnote A diagnosis of PV requires the presence of all three major criteria or the first two major criteria and the one minor criterion.

Question 50

Criterion number 2 (bone marrow biopsy) may not be required in:

Answer 50

Sustained absolute erythrocytosis: hemoglobin levels >18.5 g/dL in men (hematocrit 55.5%) or >16.5 g/dL in women (hematocrit 49.5%) If major criterion 3 and the minor criterion are present.

Question 51

The major causes of morbidity and mortality in PV

Answer 51

1. Increased incidence of vascular complications (ie, thrombosis and/or hemorrhage) 2. Progression to post-PV MF or acute leukemia/ myelodysplasia

Question 52

Major risk factors for serious vascular complications in PV

Answer 52

Age of the patient (>60 years) Previous thrombotic events

Question 53

Classifications of PV

Answer 53

**Low risk** **Intermediate risk:** age older than 60 years **High risk:** previous thrombotic events (including transient ischemic attacks)

Question 54

The most adverse additional somatic PV mutations in terms of overall, leukemia‐free, and fibrosis‐free survival in PV:

Answer 54

ASXL1, SRSF2, and IDH2 mutations

Question 55

Durable response must last at least _____ weeks

Answer 55

12 weeks

Question 56

Large improvement in symptoms means:

Answer 56

A ≥10-point decrease in MPN Symptom Assessment Form total assessment score

Question 57

Treatment for plethoric phase

Answer 57

Nonspecific myelosuppression Phlebotomies + Aspirin

Question 58

Most commonly used myelosuppressive agents

Answer 58

HU and pegylated IFN-α preparations

Question 59

Indicated for those who are resistant or intolerant to HU

Answer 59

Targeted JAK2 inhibitors

Question 60

Among treatment for spent phase this have been proven to be beneficial in prospective trials

Answer 60

JAK2 inhibitors

Question 61

Treatment for spent phase PV

Answer 61

HU Transfusion Erythropoiesis-stimulating drugs JAK2 inhibitors Hypomethylating agents Splenectomy Allogeneic stem cell transplantation

Question 62

Most common myelosuppressive agent used in the treatment of PV

Answer 62

Hydroxyurea ## Footnote initial therapy (1000–1500 mg qd) and long-term treatment (500–2000 mg qd)

Question 63

An effective therapy for controlling erythrocyte, leukocyte, and platelet counts, and it decreases the risk of thrombosis

Answer 63

Hydroxyurea

Question 64

About _____ of PV patients develop HU resistance or intolerance (ie, skin ulcers or gastrointestinal intolerance)

Answer 64

10% ## Footnote Resistance to HU has been correlated with decreased survival and a higher rate of transformation to AML or MF.

Question 65

A side effect in a small number of patients with PV, especially in areas with increased UV exposure

Answer 65

Nonmelanoma skin cancers

Question 66

Causes long-lasting marrow suppression; can be given intermittently at a dose of 2–8 mg daily for a period not exceeding several weeks

Answer 66

Busulfan

Question 67

Has increased incidence of transformation to leukemia

Answer 67

Busulfan

Question 68

Dose of Radioactive Phosphorus used in PV

Answer 68

2–4 mCi

Question 69

It could be a treatment option for older patients and patients who may be difficult to follow living in remote areas.

Answer 69

Radioactive Phosphorus

Question 70

Its use results in a decrease in JAK2V617F allelic burden and conversion from clonal to polyclonal hematopoiesis

Answer 70

IFN-α

Question 71

Drug of choice in pregnant PV patients

Answer 71

PEG-IFN-α ## Footnote Better tolerated than standard IFN-α and requires less frequent administration

Question 72

The initial treatment for patients with uncomplicated PV

Answer 72

Phlebotomy

Question 73

Recommended therapy for low-risk PV cases:

Answer 73

Phlebotomy + low-dose aspirin

Question 74

When phlebotomy is instituted, the hemoglobin may be reduced to normal or near-normal values by the removal of ______ mL of blood at one time every ______days

Answer 74

450 mL of blood at one time every 2–4 days ## Footnote Smaller amounts should be removed from patients who weigh less than 50 kg

Question 75

# TRUE OR FALSE Patients with impaired cardiovascular function are better treated with smaller phlebotomies at less frequent intervals.

Answer 75

FALSE Patients with impaired cardiovascular function are better treated with *smaller phlebotomies at more frequent intervals.*

Question 76

This treatment does not reduce the leukocyte or platelet count, nor does it affect pruritus or gout.

Answer 76

Phlebotomy

Question 77

The usual consequences of repeated phlebotomies:

Answer 77

Iron deficiency and resulting microcytosis

Question 78

# TRUE OR FALSE In patients with Chuvash erythrocytosis, the risk of stroke is independent of hematocrit and increased by phlebotomies

Answer 78

TRUE In patients with Chuvash erythrocytosis, **the risk of stroke is independent of hematocrit and increased by phlebotomies**

Question 79

Can be used in PV to decrease thrombocytosis, as an adjunct to other treatments

Answer 79

Anagrelide

Question 80

Starting dose of Anagrelide

Answer 80

0.5 or 1.0 mg given four times daily ## Footnote Average dose required to control the platelet count was **2.4 mg per day**

Question 81

# TRUE OR FALSE Control of pruritus is achieved using myelosuppression.

Answer 81

TRUE Control of pruritus is achieved using **myelosuppression**.

Question 82

Aside from myelosuppression, agents helpful for pruritus

Answer 82

Photochemotherapy with psoralens and ultraviolet light

Question 83

The study that showed that daily low-dose aspirin decreased arterial and venous thromboses, albeit incompletely.

Answer 83

ECLAP study

Question 84

# TRUE OR FALSE Aspirin should be used when the platelet count exceeds 1000–1500 × 109/L

Answer 84

FALSE Aspirin **should not be used when the platelet count exceeds 1000–1500 × 109/L**

Question 85

An oral JAK1/JAK2 inhibitor is now FDA-approved for patients with PV that is resistant or intolerant to HU.

Answer 85

Ruxolitinib

Question 86

# TRUE OR FALSE JAK2 inhibition does not change or modify the natural course of PV, but mainly ameliorates the symptoms.

Answer 86

TRUE JAK2 inhibition does not change or modify the natural course of PV, but mainly ameliorates the symptoms. ## Footnote No conclusive evidence of its benefits for prevention of thromboses and transformation to post-PV MF and AML.

Question 87

An **HDAC inhibitor** that specifically inhibits the proliferation of JAK2V617F-positive cells compared with normal cells by inhibiting hematopoietic transcription factors NFE2 and c-MYB.

Answer 87

Givinostat

Question 88

Post-PV MF usually occurs after_______ years or more

Answer 88

15 years

Question 89

The treatment of choice in patients with **early signs of MDS/AML transformation**, it is the only treatment offering the **possibility of a cure**

Answer 89

Hematopoietic Stem Cell Transplantation

Question 90

# TRUE OR FALSE Chlorambucil should no longer be used for PV therapy.

Answer 90

TRUE