MPNs

Question 1

Side effects common to all TKis

Answer 1

Cytopenias, rash, arthralgias, N/V/D, edema

Question 2

Specific side effects of Dasatanib

Answer 2

Pleural effusion, pulmonary artery hypertension

Question 3

Specific side effects of Nilotinib

Answer 3

Black box warning QTc prolongation and sudden death, pancreatitis, arterial occlusion events (CVD, PVD, at higher doses), hyperlipidemia, hyperglycemia, hyperbilirubinemia,

Liver toxicity, cytopenias, rash, fatigue, myalgias.

Question 4

Specific side effects of Imatinib

Answer 4

cardiac failure, fluids retention, liver toxicity, rash, diarrhea.

Question 5

Specific side effects of Bosutinib

Answer 5

diarrhea, fetal harm,transaminitis, no black box warning

Question 6

Specific side effects of Ponatinib

Answer 6

Arterial occlusion + venous thrombosis/hepatotoxicity, HTN, cardiac arrhythmia and hemorrhage.

• pan-BCR-ABL1 TKI inhibitor with activity against CML with T315I mutation and in those with resistance to multiple TKI inhibitors

Question 7

Treatments for Anemia in myelofibrosis

Answer 7

• ESAs (if EPO<500)
• Androgens (ex. danazol)
• Corticosteroids (if there is a hemolytic component)
• Immunomodulatory Drugs (thalidomide, lenalidomide)
• Transfusions
• Ruxolitinib (helpful for splenomegaly, symptoms and potentially survival but will likely worsen anemia so likely not in a patient with Hb ~70)

Question 8

Name 8 causes/risk factors of increased thrombotic risk in ET

Answer 8

1. Jak2
2. CVD RFs (smoking, HTN, DM2)
3. Age >60
4. WBC >11
5. Hg <120
6. Prior thrombosis
7. Male
8. BM fibrosis

Others:
Pregnancy 
Known thrombophilia 
Other cancers 
OCP/HRT

Question 9

Optimal Hct for PV patients?

Answer 9

As per Cyto-PV NEJM 2013:
All (both Male and female) < 0.45

If they ask for more specifics, then comment on:
Female < 0.42
Pregnant < 0.36

Question 10

Mutations seen in atypical CML

Answer 10

SETBP1, CSF3R, ASXL1

Question 11

Compare CAL-R in ET/PMF to JAK2-V617F

Answer 11

CAL-R- tends to be younger, higher platelet count, less thrombosis. Better survival and less anemia in PMF.

Triple negative has worst prognosis.

Question 12

Benefits of Jakavi as seen in COMFORT-1, COMFORT-2.

Answer 12

Primary end point: Reduction in spleen size by >/= 35% by 24 weeks (COMFORT-1) or 48 weeks (COMFORT-2).

Decreased splenomegaly
Decreased MF associated symptoms
Improved quality of life
May increase OS (seen in COMFORT1 (vs. placebo) at 3 and 5 year follow up analyses, but not in COMFORT2 (vs. best available therapy).

Question 13

What are two non-therapy related hemostatic laboratory abnormalities in MPNs?

Answer 13

o Acquired vWD
o Acquired APC resistance
o Platelet functional defects

Question 14

3 causes of congenital polycythemia

Answer 14

1. AD polycythemia aka EPOR mutations
2. Chuvash polycythemia (affects VHL gene causes increased EPO)
3. High affinity hemoglobin
4. Low 2,3 -BPG
5. Congenital methemoglobinemia
6. HIF2A (EPAS1 mutation)
7. Proline Hydroxylase (EGLN1 mutation)

Question 15

4 gene rearrangements seen in eosinophilic disorders and their treatments.

Answer 15

1. FIP1L1-PDGFRA (low dose imantinib)
2. FIP1L1-PDGFRB (low dose imantinib)
3. FGFR1 (bad prognosis, chemo/transplant)
4. PCM1-JAK2 (ruxolitinib)

Question 16

What is Mepolizumab and what diseases is it used in?

Answer 16

Monoclonal Ab directed against IL-5, a growth factor important for eosinophil maturation and activation.

• beneficial in glucocorticoid-sensitive HES, including idiopathic HES, lymphocytic variants of HES (L-HES), and HES/eosinophilic granulomatosis with polyangiitis (EGPA) overlap

Question 17

PDGFRA-alpha blocker that is used in systemic mastocytosis and GIST tumors?

Answer 17

Avapritinib

Question 18

5 high molecular risk genes in the MIPSS score of PMF?

Answer 18

1. IDH1
2. IDH2
3. EZH2
4. ASXL1
5. SRSF2

AEIIS
Lots of vowels for PMF

Question 19

Treatment options for symptomatic, non-transplant eligible PMF include Ruxolitinib, HU or ______. The latter of which can cause what severe and potentially fatal complication?

Answer 19

Fedratinib

• effective for reducing splenomegaly and other PMF-related symptoms,
• associated with Wernicke-like encephalopathy
• serum thiamine level should be repleted before beginning fedratinib, and levels should be checked periodically during treatment.

Fedratinib should not be given to patients with severe liver impairment, taking strong or moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors.

Question 20

WHO criteria of PV.

Answer 20

Need 3 major or 2M and 1m:

Major:

1. Hg >165 (male) or >160 (female), or Hct >0.49 (male) or >0.48 female, or inc RBC mass (>25% above ULN)
2. Jak2 V617F or Exon 12
3. BMBx w/ hypercellularity for age, w/ trlineage growth (panmyelosis) inc prominent erythroid, granulocytic and megakaryotic proliferation w/ pleomorphic, mature megakaryocytes.

Minor:
1. Abnormal serum epo

Question 21

WHO criteria of ET.

Answer 21

Need 4M or first 3 major and 1m

Major:

1) plt count >/=450
2) Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.
3) Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
4) Presence of JAK2, CALR, or MPL mutation

Minor
1.Presence of a clonal marker or absence of evidence for reactive thrombocytosis

Question 22

WHO criteria of PMF

Answer 22

Need 3 major criteria, and at least 1 minor criterion

Major

1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms
3. Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal marker,* or absence of reactive myelofibrosis

Minor
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
1. Anemia not attributed to a comorbid condition
2. Leukocytosis ≥11 × 109/L
3. Palpable splenomegaly
4. LDH increased to above upper normal limit of institutional reference range
5. Leukoerythroblastosis

Question 23

What is atypical CML?

Answer 23

• MDS/MPN overlap syndrome, characterized by absence of t(9;22).
• Presents in elderly with elevated neutrophil count but low plt and/or Hg
• BMbx- increased cellularity with no increased blasts. Also see dysplasia in , megakaryocytes and erythroids.
• Prognosis is poor.

Common mutations:
SETBP1, CSF3R, trisomy 8, ischromosome 17q.

Question 24

WHO Criteria of CNL?

Answer 24

• WBCs ≥25 x 109/L with >80% segs/bands and <10% immature precursor cells
  *** if CSF3R, only need WBC>15
• Hypercellular marrow with <5% nucleated cells being myeloblasts
• Normal neutrophil maturation with granulocytic dysplasia
• No reactive causes of neutrophilia
• No other chronic myeloid neoplasm