SM_263b: Myeloproliferative Disorders and CML Flashcards
Myeloproliferative disorders are ____, ____, ____, and ____
Myeloproliferative disorders are essential thrombocythemia, polycythemia vera, primary myelofibrosis, and chronic myeloid leukemia
- Stem cell diseases
- Thrombotic and hemorrhagic complications
- Extramedullary hematopoiesis
- Marrow fibrosis
- Leukemic transformation
Philadelphia chromosome is present in ____ and creates ____
Philadelphia chromosome is present in CML and creates a fusion gene coding for a protein with tyrosine kinase activity that promotes proliferation and prohibits apoptosis
t(9;22) creates a ___ with a ___
t(9;22) creates a Philadelphia chromosome with BCR-ABL fusion gene
____ is present in most people with myeloproliferative disorders
JAK2 V617F is present in most people with myeloproliferative disorders
- Substitution of valine to phenylalanine at codon 617
Describe pathogenesis of JAK2 mutation
JAK2 mutation
- JAK2 mutation
- JAK2 activates 3 main myeloid cytokine receptors: erythropoietin receptor, thrombopoietin receptor, and G-CSG receptor
Mutations can be heterozygous or homozygous (mitotic recombination)
TPO activates ___ then ___
TPO activates MPL than JAK2
MPL mutations ___
MPL mutations activate receptor in absence of ligand (TPO)
- Most frequent types: W515L and located on transmembrane and cytosolic domains of MPL
- Mutations typically heterozygous
Wild-type CALR is an ___
Wild-type CALR is an ER chaperone involved in quality control of proteins and calcium storage
Describe CALR pathogenesis
CALR pathogenesis
- Heterozygous mutations
- Type 1: 52 bp deletion, type 2: 5 bp insertion
- CALR mutations activate MPL receptor
Polychthemia vera is associated with molecular defects in ___ and ___
Polychthemia vera is associated with molecular defects in JAK2 V617F and JAK2 exon 12
Essential thrombocytosis is associated with molecular defects in ___, ___, and ___
Essential thrombocytosis is associated with molecular defects in JAK2 V617F, CALR, and MPL
Primary myelofibrosis is associated with molecular defects in ___, ___, and ___
Primary myelofibrosis is associated with molecular defects in JAK2 V617F, CALR, and MPL
Chronic myeloid leukemia is associated with molecular defects in ___
Chronic myeloid leukemia is associated with molecular defects in BCR-ABL
Describe essential thrombocythemia
Essential thrombocythemia
- Persistent thrombocytosis (> 450 * 109/L)
- Bone marrow with proliferating megakaryocytes: increased enlarged mature megakaryocytes
- Not meeting WHO criteria for another chronic myeloid neoplasms
- Demonstration of a clonal marker (JAK2, CALR, MPL) or no evidence of reactive thrombocytosis in evidence of clonal marker
Describe peripheral blood findings of essential thrombocythemia
Essential thrombocythemia peripheral blood
- Thrombocytosis: often marked, small to giant platelets
- Minimal to no leukocytosis
- Mild anemia but usually normal Hb
Describe bone marrow findings of essential thrombocythemia
Essential thrombocythemia bone marrow
- Normocellular to hypercellular
- Increase in megakaryocytes: large to giant, abundant cytoplasm, hyperlobulated nuclei
- Reticulin (fibrosis) and iron stains usually normal
Describe essential thrombocythemia clinical presentation
Essential thrombocythemia clinical presentation
- Microvascular disturbance (usually due to platelet hypersensitivity): headache, TIA, dizziness, visual disturbance, erythromelalgia
- Macrovascular disturbance (older age, leukocytosis, JAK2 V617F, prior thrombosis): stroke, ACS, DVT/PE, abdominal vein thrombosis
Describe the mutational profile of essential thrombocythemia
Essential thrombocythemia mutational profile
Compare true essential thrombocythemia with prefibrotic myelofibrosis
True essential thrombocythemia with prefibrotic myelofibrosis
Describe management of essential thrombocythemia
Essential thrombocythemia
- Manage CV risk factors
- Aspirin
- Cytoreduction indicated for high risk (> 60 with JAK2+ or thrombosis history)
Describe diagnosis of polycythemia vera
Polycythemia vera diagnosis
Major
- Hgb > 16.5 g/dL in men (or Hct > 49%), > 16.0 g/dL in women (Hct > 48%)
- Bone marrow biopsy showing hypercellularity for age with prominent erythroid, granulocytic, and pleomorphic megakaryocytic proliferation
- Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor
- Subnormal Epo level
Describe bone marrow findings in polycythemia vera
Polycythemia vera bone marrow findings
- Hypercellularity and tri-lineage proliferation, particularly of megakaryocytes
- Sustainable iron usually absent
- Occassional fibrosis, even at diagnosis
Describe clinical presentation of polycythemia vera
Polycythemia vera clinical presentation
- Microvascular disturbance (usually due to platelet hypersensitivity): headache, TIA, dizziness, visual disturbance, erythromelalgia
- Macrovascular disturbance (older age, leukocytosis, JAK2 V617F, prior thrombosis): stroke, ACS, DVT/PE, abdominal vein thrombosis
___, ___, and ___ are additional complications of polycythemia vera
Aquagenic pruritis, gout, and bleeding are additional complications of polycythemia vera
- Aquagenic pruritis: increased histamine levels
- Gout: increased uric acid
- Bleeding: acquired von Willebrand’s disease
Describe disease transformation of polycythemia vera
Polycythemia vera disease transformation
- Myelofibrotic phase: increases fibrosis, splenomegaly, anemia
- Acute leukemic transformation
Describe management of polycythemia vera
Polycythemia vera management
- Manage CV risk factors
- Phlebotomy: Hct < 45%
- Aspirin
- Cytoreduction in high risk patients (age ≥ 60, prior thrombosis history)
___ is used for intolerant / resistant polycythemia vera
JAK inhibition is used for intolerant / resistant polycythemia vera
This is ___ in ___
Leukoerythroblastosis in myelofibrosis
Bone marrow biopsy of myelofibrosis shows ___
Bone marrow biopsy of myelofibrosis shows hypercellularity and clustering of atypical megakaryocytes and moderate reticulin fibrosis
Describe criteria for overt primary myelofibrosis
Overt primary myelofibrosis: clinical, morphological and molecular
Major
- Megakaryocyte proliferation and atypia with fibrosis
- Absence of ET, PV, CML, MDS, or other myeloid neoplasm
- Clonal marker (JAK2 V617F, CALR, MPL)
Minor
- Leukoerythroblastosis
- Increased serum LDH
- Anemia
- Leukocytosis
- Palpable splenomegaly
Describe mutations in myelofibrosis
Myelofibrosis
- High molecular risk: IDH, EZH2, ASXL1, SRSF2, USAF1
Myelofibrosis has best prognosis when ___
Myelofibrosis has best prognosis when CALR is positive
Describe clinical presentation of myelofibrosis
Myelofibrosis clinical presentation
- Splenomegaly
- Myelofibrotic transformation
- Fatigue, pruritis, night sweats, weight loss, abdominal pain, bone pain, anemia
Describe treatment of myelofibrosis
Myelofibrosis treatment
- Thalidomide and prednisone
- Hydroxyurea
- Splenic radiation
- Monoclonal antibodies for Int-1, Int-2, and high risk disease
___ for myelofibrosis is high reward but high risk
Transplant for myelofibrosis is high reward but high risk
____ and ____ appear on CML blood smear
Left shifted myeloid and basophils appear on CML blood smear
Hypercellular bone marrow with granulocytic predominance is ___
Hypercellular bone marrow with granulocytic predominance is CML
Describe natural history of CML
Natural history of CML
- Chronic phase: leukocytosis with left shift and basophilia ± anemia, thrombocytosis / thrombocytopenia
- Accelerated phase: progressive splenomegaly, basophilia, thrombocytosis / thrombocytopenia, and increasing blasts
- Blast phase: akin to acute leukemia (myeloid or lymphoid, bi-phenotypic)
___ are used to treat CML
Tyrosine kinase inhibitor are used to treat CML
- Imatinib
- Dasatinib
- Nilotinib
- Bosutinib
- Ponatinib
Tyrosine kinase inhibitors treat CML by ___
Tyrosine kinase inhibitors treat CML by blocking binding of ATP to BCR-ABL tyrosine kinase, blocking downstream signaling, and then blocking proliferation
Describe milestones of CML treatment
CML treatment milestones
