Myeloproliferative Neoplasms

Myeloproliferative Neoplasms

MPN Part 1

What are the treatment options for primary myelofibrosis with leukemic transformation ?

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Allogeneic stem cell transplant
Hypomethylating agent

MPN Part 1
MPN

How do you manage the cytopenias of primary myelofibrosis?

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Splenectomy or radiotherapy

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MPN

What cardiopulmonary pathology can be seen with primary myelofibrosis ?

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Pulmonary hypertension

MPN
MPN

What should be calculated prior to starting treatment for primary myelofibrosis?

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Risk stratification
Incorporating leukocytosis, hemoglobin, peripheral blast percentage, age, constitutional symptoms
White blood cell count greater than 25,000 – 1 point
Hemoglobin less than 10 g/dL 2 points
Peripheral blast greater than or equal to 1% 1 point
Age greater than or equal to 65 1 point
Presence of constitutional symptoms 1 point

Scoring
0 points is low risk
1-2 equals intermediate 1
3-4 equals intermediate 2
5-6 equals high-risk

MPN
MPN

When should one use radioactive phosphorus for polycythemia?

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Never, very high risk of myeloid leukemia

MPN
MPN

What 3 situations are there that warrant interferon -2 alpha for polycythemia vera?

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Refractory pruritus, pregnancy, inability to tolerate hydroxyurea or ruxolitinib

MPN
MPN

Should fedatrinib be dose reduced in renal or hepatic impairment ?

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Renal impairment, dose reduce to 200mg daily if CrCl is <30 mL/min

MPN
MPN

Is fedatrinib indicated in primary or secondary myelofibrosis ?

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Both

MPN
MPN

Which patients would be candidates for fedatrinib ?

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Intermediate – 2 and high risk patients

MPN
MPN

What is the starting dose of fedatrinib ?

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400mg daily

MPN
MPN

What is the mechanism of action of fedatrinib ?

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JAK2 inhibitor

MPN
MPN

Which 2 interventions should always be given to polycythemia vera patients?
Baby aspirin and phlebotomy

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MPN
MPN

What dose of hydroxyurea should be started for polycythemia vera?

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500 mg every other day and then transition slowly to 2000 mg per day as tolerated

MPN
MPN

With drugs lower the incidence of secondary hematologic malignancies and increase overall survival in polycythemia vera?

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None

MPN
MPN

What agents can be considered for the treatment of polycythemia vera besides ruxolitinib and hydroxyurea?

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Pegylated interferon and busulfan

MPN
MPN

When should ruxolitinib be considered for polycythemia vera ?

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Patient’s intolerance of hydroxyurea

MPN
MPN

If patients are intolerant to hydroxyurea, what agent is available for essential thrombosis that lowers platelet counts?

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Anagrelide

MPN
MPN

What did the CYTO-PV clinical trial show?

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Using a hematocrit goal of 45% for men and 42% for women is acceptable, and there was no increase in the risk of myelodysplastic syndrome, myelofibrosis, or acute myeloid leukemia

MPN
MPN

What are the advantages of pegylated interferon -2 alpha for polycythemia?

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Increased complete response rate, lower spleen size, lower thrombosis risk

MPN
MPN

What is the incidence of acute myeloid leukemia or myelodysplastic syndrome for pipobromin at 20 years versus hydroxyurea for polycythemia ?

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50% for pipobromin
25% for hydroxyurea

MPN
MPN

Does single agent hydroxyurea cause an increase in leukemia or secondary malignancies?

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No, based on World Health Organization multi-variate analysis

MPN
MPN

What are the 2 important take-away points from the PVSG study?

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Phlebotomy alone – lower secondary cancer risk but elevated DVT risk
Phlebotomy plus alkylating agents or other agent – lower thrombosis risk but elevated cancer risk

MPN
MPN

What is the incidence of post-polycythemia myelofibrosis?

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Temperature fromPCVSG study

MPN
MPN

What is the primary disadvantage of phlebotomy alone versus phlebotomy plus cytotoxic agent for polycythemia vera ?

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Increased incidence of thrombosis

MPN
MPN

What did the PVSG study show for polycythemia vera?

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Increase survival with phlebotomy alone versus chlorambucil or radioactive phosphorus plus phlebotomy
Also, increased cancer incidence with the use of alkylating /radioactive agents

MPN
MPN

Which 2 alkylating agents can increase the risk of myelodysplastic syndrome and acute myeloid leukemia in polycythemia vera?

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Radioactive phosphorus use, pipobromin, chlorambucil

MPN
MPN

What predicts for myelodysplastic syndrome or acute myeloid leukemia evolution from polycythemia vera ?

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Use of non-hydroxyurea alkylating agents

MPN
MPN

What is the strongest predictor of myelofibrosis evolution from polycythemia vera ?

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Disease duration and the presence of leukocytosis at diagnosis

MPN
MPN

What are the top risk factors for early death from polycythemia vera?

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Age, thrombosis and leukocytosis

MPN
MPN

What are the most common causes of death for polycythemia vera patients?

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50% cardiac related death
20% solid tumor related death
13% hematologic malignancy transformation

MPN
MPN

What is the median overall survival for polycythemia vera without treatment?

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6- 18 months

MPN
MPN

With 3 different diseases can myeloproliferative neoplasms evolve into?

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Myelodysplastic syndrome, acute myeloid leukemia, myelofibrosis

MPN
MPN

Are pruritus and Erythromelalgia treated differently in polycythemia?

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Pruritus with interferon
Erythromelalgia with baby aspirin

MPN
MPN

What treatment can be offered to PCV patients who cannot tolerate hydroxyurea or Ruxolitinib besides phlebotomy?

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Interferon alfa

MPN
MPN

What 3 treatments are required for polycythemia with high risk features?

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Phlebotomy, hydroxyurea and baby aspirin

MPN
MPN

What categorizes people with polycythemia as high risk?

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History of thrombosis and age greater than 60

MPN
MPN Part 2

How do you rank the 3 risk factors for essential thrombocytosis?

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DVT> age 60 > JAK2 mutation

MPN Part 2
MPN

Which risk strata of patients should get hydroxyurea for essential thrombocytosis?

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Intermediate and high risk only, unless other risk factors are present or they have had complications

MPN
MPN

What are the 4 major risk strata for essential thrombocytosis?

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Presence of thromboembolism or age greater than 60 and JAK2 mutation = high-risk
Age > 60 and negative JAKL2 mutation = intermediate risk
Age < 60 and the presence of JAK2 mutation = low riskAge < 60, no prior history of thrombosis, no prior history of JAK2 mutation = Very low risk

MPN
MPN

When should you offer hydroxyurea to a patient with a platelet count greater than 1 million and essential thrombocytosis ?

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Presence of acquired von Willebrand disease or any arterial or venous thromboembolism

MPN
MPN

What are the prophylactic recommendations for high and intermediate risk patients with essential thrombocytosis with a history of venous or arterial thromboembolism ?

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Venous thromboembolism = hydroxyurea and Coumadin
Arterial thromboembolism = hydroxyurea and aspirin
No history of thrombocytosis = hydroxyurea and aspirin

MPN
MPN

How do you manage low and very low risk essential thrombocytosis patients with respect to prophylaxis?

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Aspirin versus observation
No indication for hydroxyurea, unless there is acquired von Willebrand disease with platelet counts greater than 1 million

MPN
MPN

How do you stratify essential thrombocytosis patients with low and very low risk disease with respect to baby aspirin use?

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Presence of vasomotor symptoms aspirin
JAK2 mutation and cardiac risk factors twice a day aspirin
JAK2 mutation or cardiac risk factors aspirin once a day
JAK2 negative and no risk factors for cardiac disease, then no treatment needed

MPN
MPN

What endpoints did aspirin prophylaxis reach for most essential thrombocytosis patients in clinical trials ?

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Reduction in non-fatal myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis
But no change in overall survival

MPN
MPN

How do hydroxyurea and anagrelide compare with respect to efficacy and side effect profile for essential thrombocytosis?

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Similar efficacy but a lower side effect profile for hydroxyurea

MPN
MPN

How do you treat essential thrombocytosis in pregnant females?

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Pegylated interferon 2-alpha

MPN
MPN

What is the mechanism of anagrelide?

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Blocks cyclicAMP phosphodiesterase

MPN
MPN

What are the side effects of anagrelide?

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Edema, tachycardia, headache

MPN
MPN

What unique response can be seen with some patients treated with interferon for essential thrombocytosis?

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Complete response of JAK2 clone

MPN
MPN

Which situation would warrant plateletpheresis in essential thrombocytosis?

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Acute arterial or venous thromboembolism

MPN
MPN

When would phosphorus-32 be a suitable option for essential thrombocytosis?

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Low lifespan on the order of 3-5 years

MPN
MPN

What is the lifetime acute myeloid risk for essential thrombocytosis patients?

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2-3%

MPN
MPN

What is the most common complication for essential thrombocytosis?

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Thrombosis

MPN
MPN

Who should get twice a day dosing aspirin for essential thrombocytosis?

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Presence of both JAK2 mutation and cardiac risk factors

MPN
MPN

How do you risk stratify high and intermediate risk essential thrombocytosis patients versus low- and very- low risk patients with respect to hydroxyurea and anti-coagulant/aspirin use?

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High and intermediate risk
Presence of venous thromboembolism – hydroxyurea and Coumadin
Presence of arterial thromboembolism – hydroxyurea and aspirin
Age greater than 60 and no thrombosis history – hydroxyurea and aspirin

Low and very low risk
Presence of vasomotor symptoms – aspirin
JAK2 mutation and cardiac disease risk factors – aspirin twice a day
JAK2 mutation or cardiac risk factors aspirin – once a day
JAK2 negative and no cardiac risk factors – observation only

MPN
MPN

Which essential thrombocytosis patients should definitely get hydroxyurea?

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Age greater than 60, all patients with thrombosis, presence of JAK2 mutation, acquired von Willebrand disease

MPN
MPN

What is the target platelet count for patients are on hydroxyurea for essential thrombocytosis ?

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100,000 -400,000

MPN
MPN

What makes a patient low versus very- low risk in essential thrombocytosis?

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Low risk – age younger than 60 and positive JAK2 mutation
Very low risk – age less than 60 and negative JAK2 mutation

MPN
MPN

What automatically makes an essential thrombocytosis patient high-risk?

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positive history of thrombosis

MPN
MPN

What are the variables in the IPSTE risk-model for essential thrombocytosis ?

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Age greater than 60, history of venous thromboembolism, presence of JAK2 , history of cardiac disease risk factors including hypertension diabetes and smoking
Age 1 point, thrombosis history 2 points, mutation 2 points, cardiac risk factors 1.
3 or more points high risk, 2 points intermediate risk, 0-1 points low risk

MPN
MPN

Which patients with essential thrombocytosis require neither hydroxyurea nor baby aspirin?

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Low-risk and very-low risk and no prior history of cardiac disease or thrombosis in the setting of JAK2 negative disease

MPN
MPN

Which multiple myeloma drug is active in refractory primary myelofibrosis?

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Lenalidomide plus prednisone
NO efficacy with bortezomib

MPN
MPN

Which biomarkers are predictive of hydroxyurea response in primary myelofibrosis?

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JAK2
48% versus 80% overall response rate

MPN
MPN

What therapy is not offered in the low versus very-low risk primary myelofibrosis?

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ruxolitinib

MPN
MPN

What differentiates low-risk and very-low risk primary myelofibrosis?

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Low risk = DIPSS low risk
Very low risk = DIPSS (low) and CALR(mut)/ASXL2(wt)

MPN
MPN

What is an important consideration for patients when they discontinue ruxolitinib?

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Discontinuation syndrome similar to sepsis

MPN
MPN

Which drugs cause major interactions with ruxolitinib?

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CYP3A4 inhibitors

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MPN

When should ruxolitinib be dose reduced for myelofibrosis?

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Severe thrombocytopenia:
Greater than 200,000 use 20 mg twice a day
100,000-200,000 use 10 mg twice a day
50,000 100,000 use 5 mg twice a day
Less than 50,000 discourage use

MPN
MPN

What is a salvage option for primary myelofibrosis patients that relapse after allogeneic stem cell transplant?

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Donor lymphocyte infusion

MPN
MPN

Which MF patients don’t benefit from allogeneic stem cell transplant?

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Low risk and intermediate risk–1

MPN
MPN

What is the best and worst mutation combination for myelofibrosis with regards to the genes CALR and ASXL2 wrt prognosis?

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CALR (WT) AND ASXL2 (MUT) = 2 years
CALR (MUT) AND ASXL2 (WT) = 10 years

MPN
MPN

Which mutation should prompt an allogenic stem cell transplant, in myelofibrosis, negative for JAK2, MPL, and CALR?

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ASXL2

MPN
MPN

What cytogenetic changes should always be tested for primary myelofibrosis?

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5q- because it predicts for a high response to lenolidamide

MPN
MPN

For myelofibrosis patients without a driver mutation, what other mutations can suggest an underlying diagnosis?

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ASXL2, IDH1/2, EZH2

MPN
MPN

What is a new mass likely to be in a patient with primary myelofibrosis ?

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Extramedullary hematopoiesis site

MPN
MPN

How do you manage pulmonary hypertension of primary myelofibrosis?

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Whole lung radiotherapy

MPN
MPN Part 3

What features predict for a high risk of leukemic transformation in patients with primary myelofibrosis ?

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IDH1, ASXL1 and SRSF2 mutations, very high-risk karyotype, age > 70 years, male sex, circulating blasts ≥ 3%,

MPN Part 3
MPN Part 3

What % of non-CML MPN will develop a second cancer ?

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10%

MPN Part 3
MPN Part 3

Did the RESUME trial show any transfusion – independence in MF ?

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No

MPN Part 3
MPN Part 3

What did the RESUME trial assess in MF ?

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Phase 3 trial of Pomalidomide in PRBC-dependent MF

MPN Part 3
MPN

Which patient risk-strata were included in the COMFORT-I trials in MF ?

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Int-2 and high-risk

MPN
MPN

Which trials showed improvements in OS with ruxolitinib in primary MF ?

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COMFORT-I and COMFORT-II

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Which patients were included in the JAKARTA trial for MF ?

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Int-2 and high risk primary MF as well as secondary – MF

MPN
MPN

What medication did the JAKARTA trial assess for MF ?

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Fedratinib

MPN
MPN

What did the ANAHYDRET trial determine for ET ?

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Anagrelide is not inferior compared to hydroxyurea in the prevention of thrombosis

MPN
MPN

What did the ANAHYDRET trial assess in ET ?

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Hydrea versus anagrelide/aspirin

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MPN

Should ruxolitinib use be discouraged if allogeneic stem cell transplant is planned for primary myelofibrosis?

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No

MPN
MPN

Is there data to support the use of combination hydroxyurea and ruxolitinib in primary myelofibrosis ?

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Yes, but non-randomized

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MPN

Which downstream pathway does JAK2 interact with besides MAPK ?

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PI3/AKT

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MPN

Does the risk of secondary malignancy increase with prolonged use of ruxolitinib in primary myelofibrosis ?

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Yes, but death incidence from primary MF grows faster

MPN
MPN

What is the most common cause of ruxolitinib discontinuation in myelofibrosis patients ?

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Lack/loss of spleen response

MPN
MPN

Which conditioning regimen is preferred for myelofibrosis transplant ?

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Fludarabine/busulfan

MPN
MPN

What is the dosing of fedratinib for primary myelofibrosis ?

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400mg daily

MPN
MPN

What cytopenia is more common with fedratinib ?

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Anemia

MPN
MPN

Can patients with primary myelofibrosis who lose a response to ruxolitinib be salvaged with fedratinib?

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Yes

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MPN

What is a concerning CNS side effect of fedratinib ?

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Encephalopathy

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MPN

What are some signs that a patient with myelofibrosis is losing a response to ruxolitinib ?

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Splenomegaly and / or cytopenias

MPN
MPN

Is ruxolitinib safe in pregnancy ?

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No

MPN
MPN

What is a rare CNS side effect that can be seen with ruxolitinib therapy ?

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PML

MPN
MPN

Which top 3 patient reported symptoms show the highest response to ruxolitinib in hydroxyurea refractory patients with PCV ?

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Day time sweating, night sweats and pruritis

MPN
MPN

What percent of patients on ruxolitinib for PCV who had progressed on hydroxyurea can maintain their response at 5 years ?

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75% but only 55% with complete hematologic response

MPN
MPN

What is the starting dose of ruxolitinib for pCV ?

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10mg twice daily

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MPN

What are some signs or symptoms of PCV progressing despite hydroxyurea therapy ?

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Hct >45% despite max dose with leukocytosis, thrombocytosis or disease related symptoms

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MPN

What are the risk factors for high-risk PCV ?

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Hx of thrombosis as well as age > 60 years old

MPN
MPN

What is the minor criteria for a WHO diagnosis for PCV ?

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Subnormal EPO

MPN
MPN

What percent of PCV patients have a JAK2 mutation ?

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95%

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MPN

Which protein does the JAK1/2 heterodimer interact with ?

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STAT

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MPN

Which ethnic group has low baseline hemoglobin levels?

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Chuvash Russians

MPN
MPN

Which mutation confers a shorter survival for essential thrombocytosis?

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MPL

MPN
MPN

What MPN condition has a CSF3R mutation?

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Chronic neutrophilic leukemia

MPN
MPN

How do CALR and JAK2 mutation compare with respect to overall survival and thrombosis risk in myeloproliferative neoplasms?

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CALR patients have lower thrombosis and better overall survival

MPN
MPN

Do you need a JAK2 mutation to determine the efficacy of ruxolitinib?

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No

MPN
MPN

What mutations should be evaluated when JAK2 V617F testing is negative in PCV?

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Exon 12

MPN
MPN

Which exons are mutated in CALR and MPL ?

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Exon 9 (CALR) and exon 10 (MPL)

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MPN

Which blood test is required for platelets greater than 1 million or active bleeding and essential thrombocytosis in ET?

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Von Willebrand factor testing

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MPN

Which risk factor carries the most weight for essential thrombocytosis?

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History of venous thromboembolism

MPN
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