Bhl Week 3: Myeloproliferative Neoplasms

Front 1

List the 4 most common MPNs.

Back 1

1. Chronic myeloid leukemia (CML)
2. Polycythemia vera (P.vera)
3. Essential thrombocythemia (ET)
4. Primary myelofibrosis (PMF)

Front 2

Which MPNs are sometimes grouped together as the "Philadelphia-negative MPNs"?

Back 2

1. P. vera
2. Essential thrombocythemia
3. Primary myelofibrosis (PMF)

Front 3

As a rule, if it looks like a chronic myeloproliferative neoplasm and it has a Philadelphia chromosome, it's.....

Back 3

CML

Front 4

Which mutation can be very helpful in confirming the presence of one of the Ph-negative MPN, especially P.vera?

Back 4

JAK2 mutation

Front 5

Which mutation is involved in CML?

Back 5

BCR-ABL1 rearrangement

(ABL is the abelson proto-oncogene; a tyrosin kinase)

Front 6

Besides CML, the other MPNs involve what kind of mutation?

Back 6

JAK2 mutation

*Does not help differentiate between the different non-CML MPNs

Front 7

What translocation is involved in the Philadelphia chromosome?

Back 7

t(9;22)

*ABL gene on chromo 9 translocated to BCR gene on 22. BCR/ABL1 fusion gene formed

Front 8

What is the result of the BCR-ABL fusion protein?

Back 8

More potent tyrosine kinase than the normal ABL protein

Front 9

What are the 2 most common breakpoints on BCR and which one results in a more potent tyrosine kinase?

Back 9

p210 --> most common. Majority of typical CML

p190 --> 2nd most common. Most Ph-(+) ALL. MOST POTENT

Front 10

What is the size of the BCR/ABL fusion protein found in most cases of CML?

Back 10

p210

Front 11

Before the development of Gleevec, CML typically went through two or three phases. What were there phases?

Back 11

1. Chronic phase
2. Accelerated phase
3. Blast crises

(occasional cases evolve into "burnt out" fibrotic phase)

Front 12

Before Gleevec came out, what was the most common stage of CML at diagnosis?

Back 12

Chronic stage
(typically lasted 3-4 yrs)

Front 13

List 3 characteristics of the chronic phase of CML.

Back 13

1. Marked granulocytosis
2. Splenomegaly
3. Systemic or hypermetabolic symptoms (fever, night sweats, weight loss, hyperuricemia)

Front 14

Which blood smear characteristics are nearly diagnostic of CML?

Back 14

1. Complete spectrum of granulocytic maturation, with a predominance of myelocytes and segmented neutrophils, with rare blasts
2. Basophilia

Front 15

How do you confirm the diagnosis of CML?

Back 15

1. Typical CBC and blood smear
2. Splenomegaly
3. Decreased LAP score
4. Increased Vit B12 level
5. Presence of Ph and/or BCR/ABL arrangement

Front 16

List 3 ways to demonstrate the BCR/ABL rearrangement. What is the most typical way?

Back 16

1. PCR-based test on blood <-- most typical
2. FISH
3. Standard cytogenetics

Front 17

What phase can occur between the chronic phase and blast crisis in CML?

Back 17

Accelerated phase
(relatively short phase)

Front 18

What is the definition of a blast crisis?

Most blast crisis have which phenotype?

Back 18

>20% blasts in blood and/or marrow

*Most have myeloid phenotype, resembling AML

Front 19

Why is it important to distinguish between a myeloid blast crisis and lymphoid blast crisis?

Back 19

Treatment is different.

Myeloid blast crisis is treated like AML
Lymphoid blast crisis is treated like ALL.

Front 20

What is the drug of choice for essentially all patients w/ chronic phase CML?

Back 20

Tyrosine kinase inhibitors (TKIs)
(Gleevec, Dasatinib, nilotinib)

Front 21

What is the mode of action of Gleevec?

How is it administered?

Back 21

Inhibits the BCR/ABL tyrosine kinase

*Administered orally

Front 22

What is the function of hydroxyurea in patients with CML?

Back 22

Palliative role:
Useful to rapidly lower the WBC count in pts with very high WBC counts

Front 23

What sort of treatment is usually reserved for CML patients who do not have a good response to Gleevec?

Back 23

Bone marrow transplant

Front 24

List 4 treatments for the chronic phase of CML.

Back 24

1. Tyrosine kinase inhibitors
2. Hydroxyurea
3. Interferon-a
4. Bone marrow transplant

Front 25

What is the only proven curative therapy for CML?

Back 25

Allogenic stem cell transplant

Front 26

What is the second most common MPN?

Back 26

Polycythemia vera

Front 27

What is the main feature of polycythemia vera?

Back 27

Marked increase in the RBC mass

Front 28

What are the most important complications and most common cause of death in P. vera?

Back 28

Thromboembolic events

Front 29

What's the difference between primary and secondary polycythemia vera?

Back 29

Primary polycythemia (p. vera) is independent of EPO, while secondary polycythemia is EPO driven

Front 30

The great majority of P. vera cases have which mutation?

Back 30

JAK2-V617F

*All cases of p. vera are related to a mutation in the JAK2 gene

Front 31

What is often used as a surrogate marker for a JAK2 mutation in patients thought to have P. vera?

Back 31

Low EPO level

Front 32

List some symptoms associated with p. vera.

Back 32

1. Increased blood viscosity
2. Splenomegaly
3. Thrombotic complications
4. Bleeding from mucous membranes or into skin
5. Pruritis
6. Hyperuricemia
7. Erythromelalgia

Front 33

What is the effect of polycythemia vera on the GI system?

Back 33

1. Predisposition to peptic ulcers
2. Massive hemorrhage
3. Hepatic vein thrombosis (Budd-Chiari syndrome)

Front 34

What is the most serious complication of P. vera?

Back 34

CNS vascular lesions

Front 35

What are some common physical exam findings associated with p. vera?

Back 35

1. "Ruddy" skin
2. Splenomegaly
3. Hypertension

Front 36

How is the diagnosis of P. vera made?

Back 36

1. Elevated Hb (men: >18.5, women: >16.5)
2. Presence of JAK2 B617F
3. Bone marrow biopsy showing hypercellularity w/ trilineage growth
4. Low serum EPO

Front 37

What is the cornerstone of treatment of P.vera?

Back 37

Phlebotomy

Front 38

What is the first agent used in patients with P.vera who can't be successfully controlled by phlebotomy alone?

Back 38

Hydroxyurea

Front 39

List 4 treatments for P.vera

Back 39

1. Phlebotomy*
2. Hydroxyurea
3. Radioactive phosphorus
4. Interferon-a

Front 40

Describe the difference between a physiologically appropriate and inappropriate increase in EPO, leading to secondary p.vera.

Back 40

Appropriate response---> due to decreased oxygenation (hypoxemia)

Inappropriate response --> due to ectopic production of EP due to renal disease or renal cysts, or tumors.

Front 41

List 4 physiologically inappropriate causes of an increase in EPO.

Back 41

1. Tumors, renal cysts, hemangiomas
2. Androgen abuse
3. EPO abuse ("blood doping")
4. Familial polycythemia

Front 42

What is the main risk associated with essential thrombocythemia?

Back 42

Main risk --> thromboembolism

*Hemorrhage is less common

Front 43

Does ET follow an indolent or aggressive course?

Back 43

Indolent course

Front 44

Is ET more common in men or women?

Back 44

About equal

Front 45

The major clinical manifestations of ET are usually related to... ?

Back 45

Thrombosis

Front 46

Is the thrombosis associated with ET usually arterial or venous?
Small or large vessels?
Which parts of the body are most commonly involved?

Back 46

Arterial
Small vessels
Neurologic and distal extremities

Front 47

What are some neurologic manifestations of ET?

Back 47

1. Headaches
2. Parasthesias
3. Transient ischemic attacks
4. May progress to definitive cerebral infarcts

Front 48

Which condition may result in digital pain, gangrene of digits, and erythromelalgia?

Back 48

ET

Front 49

Is bleeding generally mild or profuse in ET?

What is the most common site of bleeding?

Back 49

Mild bleeding

GI tract is the most common site

Front 50

When are hemorrhagic events more likely to occur with ET?

Back 50

With high platelet counts (>10^6)

Front 51

What platelet count increases the likelihood of thrombocytosis-related ET rather than reactive thrombocytosis?

Back 51

Platelet count >1.5 million/uL

(Platelet counts up to 1 million/uL are more likely to be due to reactive thrombocytosis, since it is far more common than ET)

Front 52

Why can platelet count NOT be used to differentiation ET from the other MPNs?

Back 52

Marked thrombocytosis can be seen in ANY of the MPNs

*CML is actually a more common cause of thrombocytosis than ET

Front 53

What other condition must be excluded before making the diagnosis of ET?

Back 53

CML
(More common cause of thrombocytosis than ET)

Front 54

What is the current platelet threshold for diagnosis of ET?

Back 54

>450,000/uL

Front 55

What type of patients should be treated for ET?

Back 55

Older patients (>60 yo) or patients with previous thrombotic episodes

*Young, asymptomatic patients may not require treatment

Front 56

List 5 treatment options for ET.

Which treatment is considered the treatment of choice in yount people, especially young women?

Back 56

1. Hydroxyurea
2. Asprin
3. Interferon-a <-- treatment of choice for young ppl
4. Anagrelide
5. Plateletpheresis

Front 57

How does Anagrelide work?

Back 57

It inhibits megakaryocyte maturation, effectively lowering platelet count

Front 58

Which of the MPNs often causes MASSIVE splenomegaly?

Back 58

Primary myelofibrosis (PMF)

Front 59

What is the pathyphysiology behind primary myelofibrosis?

Back 59

1. Excessive production of growth factors by neoplastic megakaryocytes
2. GF factors stimulate fibroblast proliferation and production of collagen

Front 60

What are some clinical features associated with PMF?

Back 60

1. Fatigue (due to anemia)
2. Abdominal discomfort (due to splenomegaly)
3. Bleeding (petechiae, purpura, hematamesis)

Front 61

Which MPN is associated with leukoerythroblastic rxns and teardrop RBCs on a blood smear?

Back 61

PMF

Front 62

Next to CML, which MPN has the highest incidence of acute leukemic transformation?

Back 62

PMF

Front 63

Is the treatment for PMF palliative or curative?

Back 63

Palliative

(Correct reversible factors-- iron, folate deficiencies; RBC and platelet transfusions as needed for anemia)

Front 64

What is the main risk of primary myelofibrosis?

Back 64

Bone marrow failure (cytopenias)