MPNs

Question 1

What is the frequency of JAK2 mutations in PV?

Answer 1

> 95%

Question 2

What three genes can be commonly affected in ET?

Answer 2

JAK2 (V617F or exon 12), CALR, or MPL

Question 3

What gene is commonly affected in chronic neutrophilic leukemia?

Answer 3

CSF3R

Question 4

What are the WHO diagnostic criteria for polycythemia vera?

Answer 4

Major:
1) HGB > 16.5 (men) or >16 (women) or Hct > 49% (men) or >48% (women)
2) Bone marrow with trilineage hyperplasia
3) +JAK2 (V617F or exons 12)

Minor:
1) Subnormal EPO

**Diagnosis requires all 3 major or 1 + 2 + minor criterion

Question 5

Which patients with PV should be treated with aspirin?

Answer 5

All those without a contraindication

Question 6

What is the goal Hct for patients with PV?

Answer 6

Hct < 45%, some use Hct < 42% in women

Question 7

What are cytoreductive treatment options for patients with PV?

Answer 7

• Phlebotomy (preferred in patients < 60 and no history of clot)
• Hydrea
• Pegylated interferon-alpha

Question 8

What are indications for pharmacological cytoreductive therapy in PV?

Answer 8

• Age >60
• History of VTE
• Acquired vWD or bleeding related to disease
• Frequent phlebotomy (>4 per year) or poor tolerance of phlebotomy
• Symptomatic or progressive splenomegaly
• Refractory disease related symptoms (pruritis, night sweats, fatigue

Question 9

What are the diagnostic criteria for PV?

Answer 9

Major:
1) HGb >16.5 (in men) or >16.0 (in women) or Hct >48% (>49% in women)
2) Bone marrow with trilineage hyperplasia
3) JAK2+

Minor:
- sub-normal EPO

Diagnosis requires all 3 of the major criteria or 1 and 2 + minor

Question 10

Which patients with PV should be treated with aspirin?

Answer 10

Al those without a contraindication

Question 11

In addition to aspirin, what other treatment is prescribed for patients with PV?

Answer 11

Cytoreductive - either phlebotomy or medication (Hydrea or peginterferon)

Question 12

What is the target hematocrit in patients with PV?

Answer 12

< 45% for men, < 42% for women

Question 13

Which PV patients should get pharmacological cytoreductive rather than just therapeutic phlebotomy?

Answer 13

1) Age >60
2) History of VTE
3) Acquired von Willebrand
4) Frequent phlebotomy or intolerance to phlebotomy
5) Symptomatic splenomegaly, progressive leukocytosis, or progressive symptoms

Question 14

What cytoreductive therapy is preferred in pregnancy?

Answer 14

Peginterferon

Question 15

What are second line options in PV in case of progressive disease or intolerance to first line?

Answer 15

• Ruxolitinib
• Peginterferon
• Hydrea
• Clinical trial

Question 16

What is the risk of ET transforming to myelofibrosis at 20 years? What is the risk of AML transformation?

Answer 16

MF- 5-10% at 15 years
AML- 5% at 20 years

Question 17

Compared to JAK2 mutation-carriers, how ET with CALR mutation impact risk of VTE or risk of transformation to AML?

Answer 17

1) Lower risk of thrombus
2) Similar risk of AML transformation

Question 18

What are the WHO diagnostic criteria for ET?

Answer 18

Major:
1) Plts >450
2) Bone marrow with megakaryocyte proliferation with enlarged or hyperlobulated nuclei
3) Not meeting criteria for CML, PV, PMF, MDS, or other myeloid neoplasm
4) + for JAK2, CALR, or MPL

Minor:
1) Presence of other clonal marker or absence of secondary cause

Diagnosis requires either all 4 major or 1-3 + minor

Question 19

How is very-low risk ET defined?

Answer 19

• Age < 60
• JAK2-negative
• No history of VTE

Question 20

How is low-risk disease defined?

Answer 20

• Age < 60
• JAK2+
• No history of VTE

Question 21

How is intermediate risk ET defined?

Answer 21

• Age >60
• JAK2-negative
• No history of VTE

Question 22

How is high-risk ET defined?

Answer 22

• Age >60
• JAK2+
• History of VTE

Question 23

How are very-low risk or low-risk ET treated?

Answer 23

Daily aspirin or observation

Question 24

How is intermediate-risk ET treated?

Answer 24

Aspirin

Question 25

How is high-risk ET treated?

Answer 25

Aspirin + cytoreduction

Question 26

Other than disease risk-classification, what are additional indications for cytoreductive therapy?

Answer 26

- Symptomatic or progressive splenomegaly - Symptomatic thrombocytosis - Progressive leukocytosis - Progressive disease-related symptoms - Disease-related major bleeding (acquired von Willebrand) - Symptoms not responsive to aspirin

Question 27

At what platelet count does the risk of acquired vWD increase notably?

Answer 27

Plts > 1 million

Question 28

What are potential cytoreductive agents for ET?

Answer 28

- Hydrea - Peginterferon - Anagrelide - Ruxolitinib

Question 29

How does anagrelide work?

Answer 29

Interferes with the terminal differentiation of megakaryocytes

Question 30

In what patients should anagrelide be avoided and why?

Answer 30

- Avoid in patients with cardiovascular comorbidities - Can cause fluid retention, palpitations, and pulmonary hypertension

Question 31

How is prefibrotic myelofibrosis diagnosed by the 2022 WHO criteria?

Answer 31

Major: 1) Megakaryocyte proliferation and atypical without fibrosis; increased cellularity, granulocyte proliferation, and decreased erythropoiesis 2) Not meeting criteria for other MPN’s 3) JAK2, CALR, MPL, or other clonal marker Minor: 1) Anemia 2) Leukocytosis >11 3) LDH >ULN 4) Splenomegaly Need all 3 major and at least 1 minor criteria

Question 32

How is primary myelofibrosis diagnosed according to the WHO 2022 criteria?

Answer 32

Major: 1) Megakaryocyte proliferation and atypia with reticulum and/or collagen fibrosis 2) Not meeting criteria for other MPN’s 3) JAK2, CALR, MPL, or other clonal marker Minor: 1) Leukoerythroblastosis 2) Anemia 3) LDH >ULN 4) Splenomegaly 5) Leukocytosis >11 Need all 3 major criteria + at least 1 minor criteria

Question 33

What genes are commonly mutated in myelofibrosis?

Answer 33

- JAK2 (55%) - CALR (27%) - MPL (7%) - About 10% are triple negative or other

Question 34

What are the diagnostic criteria for post-PV myelofibrosis?

Answer 34

Major: 1) Prior diagnosis of PV 2) Fibrosis grade 2-3 (or 3-4) Minor: 1) Anemia or not needing phlebotomy/cytoreduction 2) Leukoerythroblastosis 3) New/Worsening splenomegaly 4) Constitutional symptoms Need both major and at least 2 minor criteria

Question 35

What are the diagnostic criteria for post-ET myelofibrosis?

Answer 35

Major: 1) Prior ET 2) Fibrosis grade 2-3 (or 3-4) Minor: 1) Anemia 2) Leukoerythroblastosis 3) New/Worsening splenomegaly 4) Constitutional symptoms 5) LDH >ULN Need both major and at least 2 minor criteria

Question 36

What are some of the risk factors associated with poor outcomes in primary myelofibrosis based on the dynamic IPSS plus?

Answer 36

- Age >65 - Constitutional symptoms - Hgb < 10 - WBCs >25 - >1% circulating blasts - Unfavorable karyotype (complex, +8, -7/7q-, i(17q), inv(3), -5/5q, 12p-, or 11q23 rearrangement) - Plts < 100 - RBC transfusion need

Question 37

What JAK inhibitors are available for treatment of myelofibrosis?

Answer 37

- Ruxolitinib - Pacritinib - Fedratinib - Momelotinib

Question 38

What are some of the common toxicities of Ruxolitinib?

Answer 38

- Cytopenias - Lipid elevation - Infection (including TB, increase in HBV load, PML, zoster) - Nonmelanoma skin cancers

Question 39

What are some of the common toxicities of fedratinib?

Answer 39

- Wernicke’s encephalopathy - Cytopenias - Nausea/vomiting - Hepatotoxicity - Amylase and lipase elevation

Question 40

What are some of the common toxicities associated with pacritinib?

Answer 40

- CYP3A4 interactions - Diarrhea - Cytopenias - Nausea - Leg swelling

Question 41

How is myelofibrosis-associated pulmonary hypertension diagnosed and treated?

Answer 41

- Diagnosis by technetium 99m full or colloid scintigraphy - Treatment is single-fraction whole lung radiation (100 cGy)