Myeloproliferative Neoplasms (Exam III) Flashcards
definition of myeloproliferative neoplasm
Greoup of disorders that are considered clonal malignancies of the hematopoietic stem cell
Myeloproliferative neoplasm usually affects
Usually >40 years old
Myeloproliferative neoplasm
results in
- BM hyperplasia and Splenomegaly or Hepatosplenomegaly
- Dominant expression of one or more “myeloid “ cell lines
- Overproduction of one or more of the PB formed elements
Chronic Myeloid Leukemia (CML)
granulocytes
Chronic Neutrophilic leukemia
neutrophils
Chronic eosinophil (CEL) not otheriwise specified
eosinophils
Polycythemia vera (PV)
Pancytosis
Essential Thrombocytopenia (ET)
Megakaryocytes/PLT
Primary Myelofibrosis (PMF)
Fibrosos
Myeloproliferative neoplasm
Transitions
Have frequent transitions and many overlapping characteristics between diseases
Chronic Myeloid Leukemia
BCR-ABL1+
definition of CML
Chronic myeloproliferative disorder with an increase in granulocytes in peripheral blood and marked granulocytic hyperplasia in bone marrow
- PB includs: neutrophils with immature forms, eosinophils and basophils granulocytes
CML also called
- Chronic Myelogenous/ Myelocytic Leukemia
- Chronic Granulocytic Leukemia
1st human disease traced to a chromosomal abnormality
CML
Philadelphia chromosome
- identified in 90-95% of patients with CML
- Not diagnostic, also found in 5% of children and 20% of adults with ALL and 2% of patients with AML
CML pathogenesis
philadelphia chromosome
- Chromosome 22q- (shortened chromosome 22)
t(9;22)
increases proliferation and inhibits apoptosis
BCR-ABL+ gene produces
p210-tyrosine kinase
p210-kinase causes
- activation of several signaling pathways
- caused increased proliferative capacity
- leads to slightly delayed maturation and lacks responsiveness to normal growth regulators
- Prevents apoptosis (cell death) in leukemia cells
- Considered essential in the pathogenesis of CML
Atypical CML
those who don’t have BCR-ABL gene
- Different prognosis and treatment
Not all Philadelphia chrom. or BCR-ABL genes are identical
- fusion protein can result in different sizes, different outcomes and different classification
- Treatment has to be determined by individual case
CML clinical features
Can be asymptomatic or symptomatic
- common to be discovered incidentally
typical CML symptoms
- Malaise/fatigue = anemia
- Abdomen Fullness
- Loss of Apetite = splenomegaly
- Night sweats
- Weight Loss
- Bone tenderness/aching
CML phases can be
biphasic or triphasic
Chronic CML phase
- Usually diagnosed in this phase
- Disease remains stable for several years
- Responsive to chemo
Accelerated phase CML
3-5 years after onset (untreated)
Worsening clinical symptoms
- Unexplained fevers
- Significant weight loss
- Worsening Splenomegaly
- Bleeding
- Thrombosis
- Infections
Blast phase CML (Blast cell crisis)
Conversion of CML to aggressive form of acute leukemia that is difficult to treat
Chronic CML phase CBC
Increased WBC count (<100,000 microL) - Leukocytosis
Decreased Hemoglobin and Hematocrit
- anemia
- Severity is proportional to the degree of leukocytosis
Possible Thrombocytosis (EXAM) TRUE
CML lab findings Chronic Phase
Increased WBC - Leukocytosis
Increased Neutrophils with immature forms
- May resemble “shift left”, but not due to BM response to infection
- see all stages from occasional myeloblast (>2%) to segmented neutrophils
- Usually more myelocytes than metamyelocytes –> “Myelocyte Bulge”
Increased Eosinophil and Basophils
- Basophilia - one of the first indicators (>2% in chronic phase)
Possible increased PLT thrombocytosis
Normocytic, Normochromic Anemia (Low RBC)
CML Chronic phase
Additional findings
- giant platelets
- nRBCs
- Anisocytosis
- Basophilic stippling
- polychromasia
CML Chronic Phase BM
Hypercellular
- marked granulocytic hyperplasia
Blasts not significantly increased (<5%)
Increased Neutrophilic, Basophilic, Eosinophilic cells
Increased Megakaryocytes
BM - CML accelerated
- blasts increasing 5-19%
- Megkaryocyte clusters
- Fibrosis
PB - CML accelerated
- increasing blasts and promyelocytes
- basophils more or equal to 20%
- Thrombocytopenia
Worsening splenomegaly, bone pain, anemia
CML blast phase
BM
- Blasts, more or equal to 20% and in clusters
- increased fibrosis
- dysplastic features
CML blast phase
PB
Blasts >20%
conversion to Acute Leukemia
Cytogenetics CML
Detection of t(9;22)(q34;q11)(BCR-ABL+)
performed by:
- FISH = Fluorescnece in Situ Hybridization
- RT-PCR = reverse transcriptase polymerase chain reaction
RT-PCR
- extremely sensitive
- Used to detect residual disease or recurrence after treatment
CML - LAP
LOW LAP score
Stains leukoyte alkaline phosphatase activity in granules
- present in normal neutrophilic granules
- decreased/absent in malignant neutrophilic granules
-
Returns to normal or increased due to
- remission of disease with therapy
- infection
Toxic vacuoles
Leukomoid RXN: Increased
CML: Absent
Toxic granulation
Leukomoid RXN: Increased
CML: Absent
Dohle Bodies
Leukomoid RXN: Increased
CML: Absent
Eosinophilia
Leukomoid RXN: Normal
CML: Increased
Basophilia
Leukomoid RXN: normal
CML: increased
Myelocyte bulge
Leukomoid RXN: absent
CML: present
LAP score
Leukomoid RXN: high
CML: low
Ph Chromosome
Leukomoid RXN: negative
CML: positive
CML prognosis
Medial survival 4-6 years
Poor prognostic indicators predicting blast transformation
- Additional chromosomes abnormalities
- Severe hepatosplenomegaky
- Change in PLT count - Thrombocytosis to Thrombocytopenia
- Extreme leukocytosis >100,000 uL
- BM blasts >5%
- PB basophils >20%
- Tumor suppressor gene p53 - may induce drug resistance
CML treatment
Myelosuppressive treatments (cytotoxic therapy)
Tyrosine Kinase Inhibitor
Allogenic bone marrow transplant
Treatment for CML
Myelosuppressive treatments (Cytotoxic therapy)
- hydroxyurea, interferon-alpha, or busulfan tehrapy
Targeted to controlling hyperproliferation of myeloid elements by inhibiting cell division
Allogenic bone marrow transplant
CML treatment
ONLY PROVEN CURE
Transplant related mortality and Graft vs. Host disease
- worse in older patients
- have to consider risks associated
Tyrosine kinase inhibitor
CML treatment
Imatinib mesylate (Gleevec)
- inhibits proliferation, slows skin cell growht, and induces cell death
- first drug developed against a specific molecular target
- Treats all phases of CML
Chronic Neutrophilic Leukemia (CNL)
PB
major criteria: WBC count >25,000/uL
and
> 80% band or segmented neutrophils
CNL most cases
mutation CSF3R
CNL characteristics
Basophilia and Eosinophilia NOT present
Does NOT have philadelphia chromosome
LAP increased
Chronic Eosinophilic leukemia (CEL)
clonal expansion of eosinophil precusors
major criteria CEL
PB eosinophils >1,500 microL
(normal range: 0-500 microL)
Does not have Ph Chromosome
Tissue damage occurs from eosinophilic granules
Polycythemia Vera Definition (PV)
Chronic abnormaility of the hematopoietic stem cell characterized by uncontrolled proliferation of
- erythroid cells
- granulocytic cells (neutrophils)
- Megakaryocytic cells
Etiology PV
current theory:
JAK2 V617F mutation, allowing for RBC production independent of erythropoietin (found in 90-95% cases)
PV clinical features
Chronic disease with insidious onset (asymptomatic/routine doctor visit)
possible symptoms
- Thrombosis/bleeding
- Splenomegaly and/or hepatomegaly
- hyper viscosity
- Hypertension
- Gout
PV CBC + Peripheral smear
Pancytosis
- Increased RBC count, Hgb, Hct
- Increased PLT count (thrombocytosis) - abnormal morphology/fxn
- Increased relative and absolute Granulocytosis - mostly enutrophils, but can see increase in Eosinophil and Basophils
PV - BM findings
Hypercellularity with Pancytosis
- erythroid, Myeloid, Megakaryoctic Hyperplasia
Secondary Polycythemia
Increased production of RBCs due to response to other factors
- hypoxia
- Erythropoeietin (EPO) producing tumor
Relative Polycythemia
Increased RBC count due to decreased plasma volume
- dehydration/burns
AKA tertiary polycythemia
Differential diagnosis
Secondary polycythemia
secondary: RBCs only
PV: multiple cell lines
EPO
(secondary vs PV)
Secondary: increased
PV: decreased
Relative vs PV increased cells
Relative: RBCs only
PV: multiple lines
PV treatment
Therapeutic phlebotomy
- want to create a frequency (1 unit/weekly) to bring hematocrit below:
1. men <45%
2. Women <40%
other options:
- Myelosuprressive therapy
- radioactive phosphoruous (UV radiation absorbed into the BM)
Essentiak Thrombocythemia (ET) - definition
Chronic myeloproliferative disorder characteristics by marked thrombocytosis associated with abnormal platelet function and an increased risk of thrombosis and hemorrhage
Common mutations in ET
