32 terms

Myeloproliferative Disorders:

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What protein is often mutated in myeloproliferative disorders?
Tyrosine Kinases
Is maturation in-tact in myeloproliferative disorders?
yes; there is effective maturation leading to increased peripheral blood counts
Is there organomegaly?
Hepatosplenomegaly is common due to extramedullary hematopoiesis
What is the spent phase found in myeloproliferative disorders?
It is the halting of all blood cell production in the marrow and the increase in fibrosis
What condition do myeloproliferative disorders transform to?
acute leukemia
A mutation in JAK2 is associated with which types of myeoloproliferative conditions?
Polycythemia vera, essential thrombocythemia, primary myeolfibrosis
The mutation in MPL is sometimes found in:
Essential thrombocythemia and primary myelofibrosis
The BCR-Abl mutation is found in 100% of ______cases
Chronic myeloid leukemia (referred to as the philadelphia chromosome)
Describe the mutation that is characteristic of CML and how this leads to increased proliferation:
CML is characterized by the presence of the philadelphia chromosome where there is fusion of the BCR gene on chromosome 22 and the ABL oncogene on chromosome 9. This fusion leads to the formation of a chimeric protein with tyrosine kinase activity that phosphorylates downstream effectors allowing for stem cell expansion and delayed apoptosis
______ accounts for 20% of all adult leukemia cases
CML
The median age of onset of CML is:
55
What are the clinical aspects of CML:
Adult (25-60years)
Anemic
Hypermetabolism leading to weight loss
Potential night sweats
Potential abdominal discomfort due to splenomegaly
What does the peripheral blood look like in someone with CML?
Main feature: gradual increase in leukocyte count
See too many neutrophils at various stages of maturation, granulocytosis with all granulocytic precursors, and there is characteristic basophilia
What does the bone marrow biopsy look like with someone in CML?
Hypercellular with maturing granulocytic precursors
May also see an increased number of megakaryocytes
What is the median survival of someone with CML?
3-4 years
What are the possible treatments for CML?
Cure (potential): high dose of chemotherapy followed by allogenic stem cell transplantation

Targeted monoclonal Ab therapy: Imanitib or Gleevec which selectively targets BCR-ABL tyrosine kinase
What is polycythemia vera?
clonal myeloproliferative disorder with proliferation of all myeloid cell lines, but erythroid proliferation is dominant. Maturation is intact and proliferation is independent of mechanisms that normally regulate erythropoiesis. PV is strongly associated with activating point mutations in tyrosine kinase JAK2
What is the clinical presentation of PV?
Mean age of diagnosis: 60
Most symptoms are related to increased RBC mass and abnormal blood flow:
-Venous stasis, thrombosis and hemorrhage
-Hypertension
-Headache, weakness, sweating
-Intense puritis
-Increased incidence of peptic ulcer disease
The CBC of a person with PV looks like:
Increased Hg: 12-28
Increased Hematocrit: >60%
Elevated platelets
WBC normal
What are potential ways of managing PV?
Phlebotomy to reduce viscosity
Low dose aspirin
Describe essential thromocythemia:
clonal myeloproliferative disorder that involves megakaryocyte lineage. It is characterized by sustained thrombocytosis in the blood and increased numbers of large, mature megakaryocytes in the bone marrow. It is typically a diagnosis of exclusion. It is the least common of the myeloproliferative diseases often characterized by recurrent thromboses and hemorrhages caused by too many platelets and abnormal functions. Associated with JAK2 mutations and MPL mutations (receptor tyrosine kinase that is normally activated by thrombopoietin)
What are the positive and negative criteria for thrombocytopenia diagnosis according to the WHO
Positive:
-Sustained platelet count >600
-Increased megakaryocytes
Negative:
-No evidence of PV, CML, or chronic myelofibrosis
-No evidence of myelodysplastic syndrome or reactive thrombocytosis
What are the clinical aspects of thrombocythemia?
Insiduous onset with mean age range 50-60
Most present with a thrombotic event (MI or stroke)
Other symptoms include HA and dizziness and can see splenomegaly in 50% of patients
Describe the course and prognosis of thrombocythemia:
Indolent disorder characterized by long symptom free intervals interrupted by occasional life-threatening thrombotic or hemorrhagic episodes. Life expectancy may be near normal for many patients but overall survival ranges from 10-15years
Describe primary myelofibrosis:
Unique myeloproliferative disease characterized by the deposition of collagen in the bone marrow, obliterating normal cellular components and leading to cytopenia. Extramedullary hematopoiesis is found in many organs
What two genes are commonly mutated in primary myelofibrosis?
Activating JAK2 mutations and MPL
Describe the clinical presentation of primary myelofibrosis
Patients older than 60. Slow onset with presentation related to splenomegaly or anemia. Hyperurecemia which is related to increased cell turnover
Describe how the early phase of myelofibrosis differs from later stages:
early phase: no or mild splenomegaly and patients often have a mild case of anemia. WBC are increased and there is increased thrombocytosis
Later phases: increasing and progressive fibrosis in BM, splenomegaly/hepatomegaly, moderate to marked anemia, leukopenia and thrombocytopenia
What does the peripheral smear of myelofibrosis show?
Leukoerythroblastosis: see granulocytic precursors and nucleated RBC
See abnormal RBC shapes such as dacrocytes and ovalcytes
How does the bone marrow appear early in myelofibrosis versus late?
Early: increased cellularity
Late: decreased cellularity and increased fibrosis
What are the typical complications with myelofibrosis? What is the typical survival in years?
Complication: infection, thrombotic episodes and bleeding
Survival ranges from 3-5 years
What percentage of those with myeolofibrosis transform to acute leukemia?
5-20%