261 - Myeloproliferative Disorders and & CML

Question 1

List 5 common features of the myeloproliferative disorders

Answer 1

• Stem cell diseases
• Thrombotic and hemorrhagic complications
• Extramedullary hematopoiesis
• Marrow fiborsis
• Can transform to acute leukemia

Essential thrombocythemia, polycythemia very, myelofibrosis, CML

Question 2

What is the appropriate management for polycythemia vera?

Answer 2

• Phelebotomy to reduce Hct
• Aspirin
• Cytoreduction sometimes (like in high risk patients)
  *

Aspirin and phlebotomy much more helpful in PV than ET

Question 3

What are the WHO criteria for dx of essential thrombocythemia?

Answer 3

• Persistent thrombocytosis (>450 x10^9 /L) (high platelet count)
• Bone marrow w/proliferating megakaryocytes
• Clonal marker (JAK2, CALR, or MPL) - or if absent, can have no evidence of reactive thrombocytosis
• Does not meet WHO criterial for another chronic myeloid neoplasm –> need to rule out alot of other things!

Hallmark abnormality = presence of large, matrue-appearing megakaryocytes

Question 4

What is leukoerythroblastosis?

Answer 4

Circulating immature WBC and RBC

• The bone marrow has been replaced by ~something else~*
• In primary myelofibrosis, it is replaced by fibrosis and scarring that pushes the immature cells out :(*

Question 5

What are the WHO criteria for diagnosing primary myelofibrosis?

Answer 5

Need all major and 1 minor

• Major criteria
  
  1. Megakaryocyte proliferation and atypia with fibrosis
  2. Absense of another myeloid neoplasm
  3. Clonal marker (JAK2 V617F, CALR, or MPL)
• Minor criteria
  
  • Leukoerythroblastosis
  • Increased serum LDH
  • Anemia
  • leukocytosis
  • Palpable splenomegaly

Question 6

What clinical features differentiate essential thrombocythemia from prefibrotic myelofibrosis?

Answer 6

Both have sustained thrombocytosis

Prefibrotic myelofibrosis will also have:

• Anemia
• Leukocytosis
• Palpable splenomegaly
• Increased LDH

Question 7

What are the key findings on bone marrow biopsy of a patient with polycythemia vera?

Answer 7

Hypercellularity with pleiomorphic megakaryocytes (varying sizes)

No stainable iron present (exhausted from making new RBCs)

Question 8

What is the mainstay of treatment for CML?

Answer 8

Tyrosine kinase inhibitor (imatinib)

Shuts of BCR-ABL fusion product that is created due to t(9;22) translocation

Question 9

What are the findings on bone marrow biopsy in a patient with CML?

Answer 9

Hypercellular

Granulocyte predominance

Question 10

What is the treatment goal for myelofibrosis?

Answer 10

Palliation of:

• Splenomegaly
• Constitutional sx
• Anemia

JAK2 inhibitors are proably not curative, but they help with quality of life

Bone marrow transplantation is curative, but the risks often outweigh the benefits

Question 11

What is the hallmark abnormality in CML?

Answer 11

BCR-ABL1

Fusion product due to t(9;22)

Results in creation of a cytoplasmic tyrosine kinase

Question 12

What are the key findings on bone marrow biopsy of a patient with primary myelofibrosis?

Answer 12

Hypercellularity, Atypical/immature megakaryocytes, reticulin fibrosis

Question 13

How can a Calreticulin (CALR) mutation lead to a myeloproliferative disorder?

Answer 13

Wild type CALR is an ER chaperone –>

Mutant CALR may activate the MPL receptor

-> Activation of JAK2/STAT pathway

–> somehow results in thrombocytosis

Question 14

What protein is most commonly mutated in polycythemia vera?

Answer 14

JAK2

V617F mutation or exon 12 mutation

Question 15

What 3 mutations are considered drivers for essential thrombocythemia?

Answer 15

JAK2 V617F

CALR

MPL

These mutations also drive primary myelofibrosis

Question 16

How does a mutation in JAK2 V617F result in increased blood counts?

Answer 16

Normal pathway is upregulated due to loss of negative regulation

Results in ligand-independent JAK2 activation

Basically, constituitive signaling is turned on

Question 17

What are the features of CML on peripheral blood smear?

Answer 17

Too many WBC + Left shift (blasts) + increased basophils

Auer rods more associated with AML than CML

Question 18

What are the 2 most common genetic abnormalities in essential thrombocythemia, polycythemia vera, and myelofibrosis?

Answer 18

JAK2 V617F

Calreticulin (CALR) mutation

Question 19

Why does the mutational profile matter in essential thrombocythemia?

Answer 19

Risk of thrombosis depends on driving mutation

• CALR mutation -> lower risk of thrombosis
• JAK2 V617F mutation -> higher risk of thrombosis

Question 20

What are the diagnostic criteria for polycythemia vera?

Answer 20

Need all major or first 2 major and the minor

• Major
  
  1. Hgb > 16.5 in men or >16.0 in women
  2. Bone marrow biopsy: hypercellular w/erythroid, granulocytic, and pleomorphic megakaryocytes
  3. Presence of JAK2 V617F or JAK2 exon 12 mutation
• Minor
  
  • Serum EPO below normal

Question 21

What will megakaryocytes look like in:

• Essential thrombocythemia:
• Polycythemia vera:
• Primary myelofibrosis:

Answer 21

• Essential thrombocythemia: too many
• Polycythemia vera: too many and different sizes
• Primary myelofibrosis: too many and aytpical/immature

Question 22

Describe the 3 stages of CML (natural hx, without tx)

Answer 22

• Chronic phase
  
  • Leukocytosis, left shift, basophilia
  • Maybe anemia and thrombocytosis or thrombocytopenia
• Accelerated phase
  
  • Progressive splenomegaly
  • Basophilia
  • Thrombocytosis or thrombocytopenia
  • More blasts (immaturity)
• Blast phase
  
  • Acute leukemia

Question 23

What is the hallmark abnormality of essential thrombocythemia on bone marrow biopsy?

Answer 23

Presence of large, mature-appearing megakaryocytes

But must exclude other myeloproliferative disorders for dx

Question 24

What conditions are considered myeloproliferative disorders?

Answer 24

• Essential thrombocythemia
• polycythemia vera
• primary myelofibrosis
• chronic myeloid leukemia

Question 25

What genetic finding is diagnostic for chronic myeloid leukemia?

Answer 25

t(9,22)

Philadelphia Chromosome