Lec 14 Myeloproliferative Neoplasms Flashcards
What is the philadelphia chromosome?
translocation t(9;22) –> sign of chronic myelogenous leukemia
What is effect of philadelphia chromosome?
have bcr-abl hybrid fusion gene
causes constitutive tyrosine kinase activity + turns on oncogenic signaling pathway
WHat is median age of CML?
64 [peak age 45-85]
What do you see in CML clinically?
- uncontrolled proliferation of granulocytes –> high neutrophils, metamyelocytes, basophils
splenomegaly
What is the triphasic course of CML?
- chronic phase
- accelerated phase
- blast crisis –> AML/ALL
What are myelodysplastic syndromes?
clonal stem cell disorders characterized by refractory cytopenias
at risk for evolving to AML/ALL
What are risk factors for MDS?
- ionizing radiation
- benzene
- cigarette smoke
- chemo drugs
What are clinical manifestations of MDS?
pancytopenia –> anemia, bleeding, infection
What do you see on peripheral blood smear with MDS?
- hypogranulation and hyposegmentation of neutrophils [pelger huet cells]
macrocytosis of RBCs
What is treatment for MDS?
- transfusion of blood/platelets
- 5 azacytidine + decitabine
- allogenic stem cell transplant
What is important feature of the myeloproliferative neoplasms?
have excessive proliferation but normal differentiation and maturation of cells
What is the pathogenesis of philadelphia chromosome in CML?
- ATP binding to bcr-abl oncoprotein –> phosphorylation of tyrosine residues
- decreased adhesion of progenitors to bone marrow stroma
- growth factor independent proliferation
- resistance to apoptosis
- porliferative growth advantage
How does CML usually present?
often asymptomatic w/ incidental high WBC on routine CBC
or can present with fevers, night sweats, bone pain, LUQ pain, early satiety secondary to splenomegaly
What happens in the chronic phase of CML?
- granulocytosis
- thrombocytosis
- basophilia
- splenomegaly secondary to extramedullary hematopoiesis
lasts 3 years
What happens in the progressive phase of CML?
after 3 years in chronic phase –> progressive increase in blood counts and splenomegaly; cytogenetic abnormalities occur
What happens in blastic phase of CML?
becomes indistinguishable form acute leukemia –> majority transform to AML; usually rapidly fatal
What do you see on CBC in CML?
granulocytosis
thrombocytosis
basophilia
normal or decreased hemoglobin
What do you see on peripheral blood in CML?
granulocytes at all stage of maturation = looks like bone marrow aspirate; increased megakaryocytes
What do you see on FISH in CML?
presence of bcr-abl fusion gene
What is differential diagnosis of CML?
- reactive granulocytosis –> absence of philadelphia chromosome, high LAP in leukamoid rxn
What is treatment for CML?
imatinib = inhibitor of bcr-abl tyrosine kinase
interferon alpha
hydroxyurea
What is usually the reason for resistance in CML?
mutation in ABL kinase domain [T315I]
What is treatment for resistant CML?
ponatinib
What is only curative treatment for CML?
allogenic hematopoietic stem cell transplant
How do you diagnose CML?
FISH or cytogenetic analysis or RT-PCR
What is normal function of JAK?
intermediate between membrane receptors and signaling molecules; become phosphorylated/activated by growth factors –> in turn activate STAT transcription factors –> increase survival, proliferation, differentiation
What disease associated with JAK2 mutation?
- polycythemia vera in 100%
- essential thrombocytosis and myelofibrosis in 30-50%
What is polycythemia vera?
clonal disorder of autonomous RBC proliferation –> increased hct, RBC, granulocytosis, thrombocytosis, splenomegaly
What is spurious polycythetmia?
presence of high hematocrit resulting from decreased plasma volume [RBC volume is normal]
in pts on diuretic therapy or in smokers
What EPO levels in primary vs secondary polycythemia?
low in primary; high in secondary
Who gets polycythemia vera?
avg age 60
What are clinical features of polycythemia vera?
- dizziness, headache, tinnitus from hyperviscosity secondary to increased hematocrit
- post bath itching
- increased basophils
What are some complications of polycythemia vera?
erythromelalgia –> seever burning pain and reddish/bluish coloration due to episodic blood clots in vessels of extremities
venous and arterial thrombosis –> budd chiari
transofrmation to AML
thrombosis
high or low or normal MCV in polycythemia vera?
low MCV secondary to iron deficiency
What is treatment for polycythemia vera?
anti-platelet agents =
What chromosomes associated with most common cytogenetic abnormalities in polycythemia vera?
chr 9 and chr 20
What is characteristic finding in polycythemia vera?
endogenous erythroid colonies
What are some causes of secondary polycythemia?
- hypoxia
- abnormal hemoglobin [high affinity]
- EPO producing tumors/cysts
What are some clinical features of primary polycythemia that distinguish it from secondary?
secondary does not have: splenomegaly, leukocytosis, thrombocytosis, icnreased risk thrombosis/bleeding
secondary = has high EPO
What is treatment for polycythemia vera?
- phlebotomy to decrease blood viscosity
- myelosuppression: hydroxyurea, anegrelide, aspirin
Who gets essential thrombocythemia?
female > male
median age 60
What is pathogenesis of essential thrombocythemia?
specific for overproduction of abnormal platelets; have JAK2 mutation in 50%
What are clinical features of essentail thrombocytsosis?
- thrombocytosis [> 1 mil platelets]
- splenomegaly
- thrombosis
- bleeding
- transofrmation to myelofibrosis or polycythemia vera
- transofrmation to AML
What is primary myelofibrosis?
clonal progressive fibrosis of the bone marrow; extramedullary hematopoiesis; massive hepatosplenomegaly
What is pathoegensis of primary myelofibrosis?
initially have high granulocyte and platelet counts –> develop mbone marrow failure and get pancytopenia
What causes the marrow fibrosis in primary myelofibrosis?
stimulation of marrow fibroblasts by platelet dervied transforming growth factor beta produced by neoplastic megakaryoctyes
What are the clinical manifestations of primary myelofibrosis?
anemia, thrombocytopenia, splenomegaly
What do you see on peripheral smear in primary myelofibrosis?
teardrop shaped RBCs, nucleated RBCs
What is significant complication of PMF?
can develop acute leukemia
Does essential thrombocytosis progress to acute leukemia?
not very often
