MPN

Question 1

Treatment for symptomatic PMF

Answer 1

• Ruxolitinib
• Peginterferon alfa-2a
• Hydroxyurea, if cytoreduction would be symptomatically beneficial
• Pacritinib (if platelets < 50 x 109/L)
• Momelotinib (category 2B)

Question 2

If asymptomatic, monitor for signs and symptoms of disease progression every _____

Answer 2

3-6 months

Question 3

Evaluation for allogeneic HCT is recommended for

Answer 3

• Patients with low platelet counts
• Complex cytogenetics

Question 4

Treatment for Higher Risk PMF, Plt >50, with symptomatic splenomegaly and/or constitutional symptoms

ALWAYS ASSESS IF TRANSPLANT CANDIDATE

Answer 4

• Ruxolitinib (category 1)
• Fedratinib (category 1)

Others:
* Momelotinib
* Pacritinib (category 2B)

Question 5

Treatment for Higher Risk PMF, Plt <50

ALWAYS ASSESS IF TRANSPLANT CANDIDATE

Answer 5

• Pacritinib (category 1)

Other recommended regimen:
Momelotinib (category 2B)

Question 6

MANAGEMENT OF MF-ASSOCIATED ANEMIA

Symptomatic splenomegaly and/or constitutional symptoms currently controlled on a JAK inhibitor

Answer 6

Preferred regimen
* Clinical trial

Other recommended regimens
* Ruxolitinib combination
Add luspatercept-aamt
Add erythropoiesis-stimulating agents (ESAs) (if serum EPO < 500 mU/mL)
Add danazol (category 2B)

Useful in certain circumstances
* Change to momelotinib
* Change to pacritinib

Question 7

MANAGEMENT OF MF-ASSOCIATED ANEMIA

Symptomatic splenomegaly and/or constitutional symptoms currently not controlled

Answer 7

Preferred regimens
* Clinical trial
* Momelotinib

Other recommended regimens:
* Pacritinib
* Ruxolitinib combination
Add luspatercept-aamt
Add erythropoiesis-stimulating agents (ESAs) (if serum EPO < 500 mU/mL)
Add danazol (category 2B)

Question 8

MANAGEMENT OF MF-ASSOCIATED ANEMIA

Anemia and no symptomatic splenomegaly and/or constitutional symptoms

Answer 8

Preferred regimen
* Clinical trial

Other recommended regimens
* Luspatercept-aamt
* ESAs (if serum EPO <500 mU/mL)
* Danazol
* Momelotinib (category 2B)
* Pacritinib (category 2B)

Question 9

Useful for del(5q)

Answer 9

Lenalidomide + prednisone

Question 10

Medication that requires prostate cancer screening and monitoring of LFTs as well as the use of concomitant medications such as statins are recommended over concerns for increased risk of rhabdomyolysis

Answer 10

Danazol

Question 11

DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM (DIPSS)

Answer 11

• Age
• White blood cell count
• Hemoglobin, g/dL ≥10 <10
• Peripheral blood blast, %
• Constitutional symptoms

Low 0
Intermediate-1 (INT-1) 1 or 2
Intermediate-2 (INT-2) 3 or 4
High 5 or 6

Question 12

DIPSS-PLUS

Answer 12

• DIPSS low-risk 0
• DIPSS intermediate-risk 1 (INT-1) 1
• DIPSS intermediate-risk 2 (INT-2) 2
• DIPSS high-risk 3
• Platelets < 100 x 109/L 1
• Transfusion need 1
• Unfavorable karyotype 1

Low 0
Intermediate-1 (INT-1) 1
Intermediate-2 (INT-2) 2 or 3
High 4 to 6

Question 13

Unfavorable karyotype (in DIPSS Plus)

Answer 13

• Complex karyotype
• Sole o ttwo abnormalities that include
• trisomy 8
• 7/7q-
• i(17q)
• -5/5q-
• 12p-
• inv(3),
• 11q23 rearrangement

Question 14

MUTATION-ENHANCED IPSS (MIPSS-70) FOR PATIENTS WITH PMF AGE ≤70 YEARS

Answer 14

• Hemoglobin < 10 g/dL 1
• Leukocytes >25 x 109/L 2
• Platelets < 100 x 109/L 2
• Circulating blasts ≥2% 1
• Bone marrow fibrosis grade ≥ 2 1
• Constitutional symptoms 1
• CALR type-1 unmutated genotype 1
• High-molecular-risk (HMR) mutations 1
• ≥2 HMR mutations 2

Question 15

High-molecular-risk (HMR) mutations

Answer 15

• ASXL1
• EZH2
• SRSF2
• IDH1/2

SEAI

Question 16

MUTATION AND KARYOTYPE-ENHANCED IPSS
(MIPSS-70+ VERSION 2.0) FOR PATIENTS WITH PMF

Answer 16

• Severe anemia (Hemoglobin < 8 g/dL in women and < 9 g/dL in men) 2
• Moderate anemia (Hemoglobin 8–9.9 g/dL in women and 9–10.9 g/dL in men) 1
• Circulating blasts ≥2% 1
• Constitutional symptoms 2
• Absence of CALR type 1 mutation 2
• HMR mutations
• ≥2 HMR mutations 3
• Unfavorable karyotype 3
• Very-high-risk (VHR) karyotype 4

Very low 0
Low 1–2
Intermediate 3–4
High 5–8
Very high ≥9

Question 17

Unfavorable karyotype (in MIPSS-70+ Version 2.0)

Answer 17

• Any abnormal karyotype other than normal karyotype
• Sole abnormalities of:
• 20q-
• 13q-
• +9
• chromosome 1 translocation/duplication,
• -Y or sex chromosome abnormality other than –Y

Question 18

VHR karyotype:

Answer 18

• Single/multiple abnormalities of −7
• i(17q)
• inv(3)/3q21
• 12p−/12p11.2
• 11q−/11q23
• Other autosomal trisomies not including + 8/+9 (eg, +21, +19)

Question 19

MYELOFIBROSIS SECONDARY TO PV AND ET-PROGNOSTIC MODEL (MYSEC-PM)

Answer 19

• Age at diagnosis 0.15 per patient’s year of age
• Hemoglobin < 11 g/dL 2
• Circulating blasts ≥3% 2
• Absence of CALR type 1 mutation 2
• Platelets < 150 x 109/L 1 Constitutional symptoms 1

Low <11
Intermediate-1 (INT-1) ≥11 and <14
Intermediate-2 (INT-2) ≥14 and <16
High ≥16

Question 20

POLYCYTHEMIA VERA

Low-risk:

High-risk:

Answer 20

Low-risk
* Age < 60 years and no prior history of thrombosis

High-risk
* Age ≥ 60 years and/or prior history of thrombosis

Question 21

TREATMENT FOR LOW-RISK POLYCYTHEMIA VERA

Answer 21

• Manage cardiovascular risk factors
• Aspirin (81–100 mg/day)
• Phlebotomy (to maintain hematocrit < 45%)

Aspirin twice daily may be considered for patients with refractory symptoms

Question 22

TREATMENT FOR HIGH-RISK POLYCYTHEMIA VERA

In addition to Aspirin, Phlebotomy

Answer 22

Preferred regimens:
* Hydroxyurea
* Ropeginterferon alfa-2b-njft

Other recommended regimen:
* Peginterferon alfa-2a
Useful in certain circumstances:
* Ruxolitinib

Question 23

FDA approved for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.

Have activity after inadequate response or loss of response to other agents besides hydroxyurea

Answer 23

Ruxolitinib

Question 24

MIPSS-PV

Answer 24

• Thrombosis history 1
• Leukocyte count ≥15x109/L 1
• Age >67 2
• Adverse mutations (SRSF2) 3

Low 0–1
Intermediate 2–3
High ≥4

Question 25

# ESSENTIAL THROMBOCYTHEMIA Very-low-risk Low-risk Intermediate-risk High-risk

Answer 25

**Very-low-risk** * Age ≤60 years, no JAK2 mutation, no prior history of thrombosis **Low-risk** * Age ≤60 years, with JAK2 mutation, no prior history of thrombosis **Intermediate-risk** * Age ˃60 years, no JAK2 mutation, no prior history of thrombosis **High-risk** * History of thrombosis at any age or age >60 years with JAK2 mutation

Question 26

TREATMENT FOR **VERY-LOW-RISK** OR **LOW-RISK** OR **INTERMEDIATE-RISK** ESSENTIAL THROMBOCYTHEMIA

Answer 26

* Manage cardiovascular risk factors * Aspirin (81–100 nmg/day) for patientsb with vasomotor/microvascular disturbances

Question 27

TREATMENT FOR **HIGH-RISK** ESSENTIAL THROMBOCYTHEMIA | In addition to **Aspirin**

Answer 27

Hydroxyurea ## Footnote Other recommended regimens for cytoreductive therapy: * Peginterferon alfa-2a * Anagrelide

Question 28

Can be considered for patients in need of cytoreductive therapy who are **younger** or **pregnant** or who **defer hydroxyurea**

Answer 28

Peginterferon alfa-2a

Question 29

Used in emergent situations, eg, severe thrombocytosis-related neurologic complications

Answer 29

Plateletpheresis

Question 30

MIPSS-ET

Answer 30

* Male sex 1 * Leukocyte count ≥11 x 109/L 1 * Adverse mutations (SRSF2, SF3B1, U2AF1, TP53) 2 * Age >60 4 ## Footnote Low 0–1 Intermediate 2–5 High ≥6

Question 31

Treatment for **Accelerated/ blast phase MPN** ## Footnote **MPN-accelerated phase** (blasts 10%– 19% in peripheral blood or bone marrow) **MPN blast phase** (blasts ≥20% in peripheral blood or bone marrow)

Answer 31

HCT

Question 32

Treatment for **Accelerated/ blast phase MPN** *Not a candidate for transplant*

Answer 32

* Clinical trial * HMA ± JAK inhibitors * HMA + venetoclaxd * Low-intensity chemotherapy

Question 33

# CRITERIA PMF, early/prefibrotic stage (pre-PMF)

Answer 33

**Major criteria** 1. Bone marrow biopsy showing megakaryocytic proliferation and atypia, bone marrow **fibrosis grade < 2, increased age-adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased erythropoiesis** 2. JAK2, CALR, or MPL mutation or presence of another clonal marker or absence of reactive bone marrow reticulin fibrosis 3. Diagnostic criteria for BCR::ABL1-positive CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms are not met **Minor criteria** * Anemia not attributed to a comorbid condition * Leukocytosis ≥11 x 109/L * Palpable splenomegaly * LDH level above the above reference range ## Footnote The diagnosis of pre-PMF or overt PMF requires **all 3 major criteria** and at least **1 minor** criterion confirmed in **2 consecutive determinations**

Question 34

PMF, overt fibrotic stage

Answer 34

**Major criteria** 1. Bone marrow biopsy showing megakaryocytic proliferation and atypia, accompanied by **reticulin and/or collagen fibrosis grades 2 or 3** 2. JAK2, CALR, or MPL mutation or presence of another clonal marker or absence of reactive myelofibrosis 3. Diagnostic criteria for ET, PV, BCR::ABL1-positive CML, myelodysplastic syndrome, or other myeloid neoplasms are not met **Minor criteria** * Anemia not attributed to a comorbid condition * Leukocytosis ≥ 11 x 109/L * Palpable splenomegaly * LDH level above the above reference range * **Leukoerythroblastosis** ## Footnote The diagnosis of pre-PMF or overt PMF requires **all 3 major criteria** and at least **1 minor** criterion confirmed in **2 consecutive determinations**

Question 35

Morphology of megakaryocytes in PMF:

Answer 35

* Small to giant megakaryocytes with a prevalence of severe maturation defects (cloud-like, hypolobulated, and hyperchromatic nuclei) * Presence of abnormal large dense clusters (mostly >6 megakaryocytes lying strictly adjacent)

Question 36

# CRITERIA PV

Answer 36

**Major criteria** 1. Elevated hemoglobin concentration or elevated hematocrit or increased red blood cell mass 2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (**panmyelosis**), including prominent erythroid, granulocytic, and increase in pleomorphic, mature megakaryocytes without atypia 3. Presence of JAK2 V617F or JAK2 exon 12 mutation **Minor criterion** * Subnormal serum erythropoietin level ## Footnote The diagnosis of PV requires either all **3 major** criteria or the **first 2 major criteria plus the minor criterion**

Question 37

Diagnostic thresholds for PV: Hemoglobin: Hematocrit: Red blood cell mass:

Answer 37

Hemoglobin: **>16.5 g/dL** in men and **>16.0** g/dL in women Hematocrit: **>49%** in men and** >48%** in women Red blood cell mass: **>25%** above mean normal predicted value

Question 38

A bone marrow biopsy may not be required in patients with

Answer 38

* Sustained absolute erythrocytosis (hemoglobin concentrations of **>18.5 g/dL** in men or **>16.5 g/dL** in women and hematocrit values of **>55.5%** in men or **>49.5%** in women) and * Presence of a JAK2 V617F or JAK2 exon 12 mutation

Question 39

# CRITERIA ET

Answer 39

**Major criteria** 1. Platelet count **≥450 × 109/L** 2. Bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage, with **increased numbers of enlarged, mature megakaryocytes with hyperlobulated staghorn-like nuclei**, infrequently dense clusters; no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; no relevant bone marrow fibrosis 3. Diagnostic criteria for BCR::ABL1-positive CML, PV, PMF, or other myeloid neoplasms are not met 4. JAK2, CALR, or MPL mutation **Minor criteria** * Presence of a clonal marker or absence of evidence of reactive thrombocytosis ## Footnote The diagnosis of ET requires either **all major criteri**a or the first **3 major criteria plus the minor criteria**

Question 40

Reactive causes of thrombocytosis

Answer 40

* Iron deficiency * Chronic infection * Chronic inflammatory disease * Medication * Neoplasia * History of splenectomy

Question 41

Symptom response requires ____% reduction in the MPN-SAF TSS.

Answer 41

≥50%

Question 42

Iron chelation could be considered for patients who have received > ______ transfusions and/or ferritin ______ ng/mL in patients with lower-risk MF.

Answer 42

> 20 transfusions and/or Ferritin >2500 ng/mL ## Footnote However, the role of iron chelation remains unclear.

Question 43

Consider this vaccine for patients on, or prior to, treatment with a JAK inhibitor

Answer 43

Recombinant (killed) zoster vaccine

Question 44

Used in MPN-associated bone pain due to their efficacy in the treatment of growth-factor–related bone pain

Answer 44

Loratadine and nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen)

Question 45

All females with PV should maintain hematocrit, ideally, below the gestational range:

Answer 45

* < 41% trimester 1 * < 38% trimester 2 * < 39% trimester 3

Question 46

Definition of High-Risk Pregnancy in PV or ET

Answer 46

* Previous venous and/or arterial thrombosis with/without pregnancy * Previous hemorrhage due to PV or ET * Previous pregnancy complications: - Unexplained death of a morphologically normal fetus ≥ 10 weeks of gestation. Premature delivery of a morphologically normal fetus at < 34 weeks of gestation due to: ◊ Severe preeclampsia or eclampsia defined according to standard criteria ◊ Recognized features of placental insufficiency - ≥3 unexplained consecutive miscarriages at < 10 weeks of gestation, without anatomic, hormonal, or chromosomal abnormalities - Unexplained intrauterine growth restriction - Significant antepartum or postpartum hemorrhage

Question 47

Recommendations for the Management of High-Risk Pregnancy

Answer 47

Treatment to start (continue) when pregnancy test is positive, and pregnancy is considered high risk: * Low-dose aspirin daily * Prophylactic LMWH throughout pregnancy and for 6 weeks postpartum * Cytoreductive therapy with interferon or peginterferon alfa-2a

Question 48

# PV and ET Complete response is defined as:

Answer 48

* Hematocrit less than 45% without phlebotomy * Platelet count ≤400 x 109/L * WBC count ≤10 x 109/L * No disease-related symptoms ## Footnote **Partial response** is defined as hematocrit less than 45% without phlebotomy or response in three or more of other criteria.