263 - Myeloproliferative Disorders and & CML Flashcards
List 5 common features of the myeloproliferative disorders
- Stem cell diseases
- Thrombotic and hemorrhagic complications
- Extramedullary hematopoiesis
- Marrow fibrosis
- Can transform to acute leukemia (all progressive diseases)
Essential thrombocythemia, polycythemia vera, myelofibrosis, CML
What is the appropriate management for polycythemia vera?
Phlebotomy (to control viscosity)
Aspirin (to lower vascular risk)
Cytoreduction sometimes
Aspirin and phlebotomy much more helpful in PV than ET
What are the WHO criteria for dx of essential thrombocythemia?
- Persistent thrombocytosis (>450 x10^9 /L)
- Bone marrow w/proliferating megakaryocytes
- Clonal marker (JAK2, CALR, or MPL) - if absent, no evidence of reactive thrombocytosis
- Does not meet WHO criterial for another chronic myeloid neoplasm
Hallmark abnormality = presence of large, mature appearing megakaryocytes
What is leukoerythroblastosis?
Circulating immature WBC and RBC.
Seen in primary myelofibrosis
- The bone marrow has been replaced by ~something else~*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 :(*
What are the WHO criteria for diagnosing primary myelofibrosis?
Need all major and 1 minor
- Major criteria
- Megakaryocyte proliferation and atypia with fibrosis
- Absense of another myeloid neoplasm
- Clonal marker (JAK2 V617F, CALR, or MPL)
- Minor criteria
- Leukoerythroblastosis
- Increased serum LDH
- Anemia
- leukocytosis
- Palpable splenomegaly
What clinical features differentiate essential thrombocythemia from prefibrotic myelofibrosis?
Both have sustained thrombocytosis. ET has mature large megakaryocytes. Myelofibrosis has weird looking megakaryocytes.
Prefibrotic myelofibrosis will also have:
- Anemia
- Leukocytosis
- Palpable splenomegaly
- Increased LDH
What are the key findings on bone marrow biopsy of a patient with polycythemia vera?
Hypercellularity with pleiomorphic megakaryocytes (varying sizes)
No stainable iron (exhausted from making new RBCs)
What is the mainstay of treatment for CML?
Tyrosine kinase inhibitor (imatinib)
Shuts of BCR-ABL fusion product that is created due to t(9;22) translocation
What are the findings on bone marrow biopsy in a patient with CML?
Hypercellular
Granulocyte predominance
What is the treatment goal for myelofibrosis?
Palliation of:
- Splenomegaly
- Constitutional sx
- Anemia
JAK2 inhibitors are proably not curative, but they help
Bone marrow transplantation is curative, but the risks often outweigh the benefits
What is the hallmark abnormality in CML?
BCR-ABL1
Fusion product due to t(9;22)
Results in creation of a cytoplasmic tyrosine kinase
What are the key findings on bone marrow biopsy of a patient with primary myelofibrosis?
Hypercellularity
Atypical/immature megakaryocytes
Fibrosis
How can a Calreticulin (CALR) mutation lead to a myeloproliferative disorder?
Wild type is an ER chaperone
Mutant may activate the MPL receptor
-> Activation of JAK2/STAT pathway
Rogue cytokine activity also possible
What protein is most commonly mutated in polycythemia vera?
JAK2
V617F or deletion of exon 12
What 3 mutations are considered drivers for essential thrombocythemia?
JAK2 V617F
CALR
MPL
These mutations also drive primary myelofibrosis
How does a mutation in JAK2 V617F result in increased blood counts?
Normal pathway is upregulated due to loss of negative regulation
Results in ligand-independent JAK2 activation
Basically, constituitive signaling is turned on
What are the features of CML on peripheral blood smear?
Too many WBC + Left shift (blasts) + basophilia
- Auer rods more associated with AML than CML*
- Thank you @Will Schwartz!*
What are the 2 most common genetic abnormalities in essential thrombocythemia, polycythemia vera, and myelofibrosis?
JAK2 V617F
Calreticulin mutation
What are the clinical concerns associated with polycythemia vera? (5)
- Vascular (thromboses)
- Aquagenic pruitis
- Gout
- Bleeding
- Transformation to AML
List 4 myeloproliferative disorders
Essential thrombocythemia
Polycythemia very
Primary myelofibrosis
Chronic myeloid leukemia
Why does the mutational profile matter in essential thrombocythemia?
Risk of thrombosis depends on driving mutation
CALR mutation -> lower risk of thrombosis
JAK2 V617F mutation -> higher risk of thrombosis
What are the diagnostic criteria for polycythemia vera?
Need all major or first 2 major and the minor
- Major
- Hgb > 16.5 in men or >16.0 in women
- Bone marrow biopsy: hypercellular w/erythroid, granulocytic, and pleomorphic megakaryocytes
- Presence of JAK2 V617F or JAK2 exon 12 mutation
- Minor
- Serum EPO belo normal
What will megakaryocytes look like in:
- Essential thrombocythemia:
- Polycythemia vera:
- Primary myelofibrosis:
- Essential thrombocythemia: too many
- Polycythemia vera: too many and different sizes
- Primary myelofibrosis: too many and aytpical/immature
Describe the 3 stages of CML (natural hx, without tx)
- 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
What is the hallmark abnormality of essential thrombocythemia on bone marrow biopsy?
Presence of large, mature-appearing megakaryocytes
But must exclude other myeloproliferative disorders for dx
