Myeloproliferative Neoplasms (MPNs) Flashcards
Clonal hematopoietic stem cell diseases with expansion, excessive production and over accumulation of erythrocytes, granulocytes and platelets in some combination; usually aquired
Myeloproliferative neoplasms (MPNs)
MPNs are predominantly ____, not acute
Chronic
Disease with overproduction of granulocytes; the cells do differentiate; clonal disorder of HSC (hematopoietic stem cell line)
Chronic Myelogenous Leukemia (CML)
Disease w/ overproduction of erythrocytes
Polycythemia Vera (or Polycythemia Ruba Vera) (PV)
Disease w/ increased megakaryopoiesis and thrombocytosis
Essential Thrombocythemia (ET)
Combination of overproduction of hematopoietic cells and ineffective hematopoiesis with resultant PB cytopenias; fibrosis in BM
PMF
Characterized by acquired structural chromosomal abnormality: Philadelphia chromosome t(9;22)(q34;q11.2), creates the fusion gene BCR-ABL1
CML
Which c’some is the derivative c’some in t(9;22) in CML?
C’some 22
Unique chimeric gene in CML that codes from a protein with enhanced tyrosine kinase activity which leads to increased proliferation and a loss of apoptotic functions
BCR/ABL1
Laboratory findings in CML PB
- Mk’d leukocytosis
- Bimodal granulocyte pattern (hallmark)
- Basophila (eosinophils can be higher too)
- Rare nRBCs
- +/- micromegakaryocytes
- ↑ LD and uric acid
- ↓ LAP (stain)
What enzyme is found w/in secondary granules of neutrophils?
Leukocyte ALKALINE phosphatase (LAP)
Philadelphia C’some
t(9;22)(q34; q11.2)
CML
- Theory of pathogenesis
ABL proto-oncogene from band q34 of c’some 9 is moved to the BCR region of band q11 on c’some 22
How do you score the LAP stain? KNOW HOW TO CALCULATE
Score 100 cells from 0-4+ and total the scores; 4+ being a cell that has a lot of secondary granules
What is a normal LAP score?
20-100
Is the LAP increased or decreased in untreated CML?
Decreased
Is the LAP score increased or decreased in a leukemoid reaction?
Normal to increased
Is the LAP increased or decreased in pregnancy and Polycythemia Vera?
Increased
What do lab findings look like in CML BM?
- Mk’d hypercellularity
- ↓ normobloasts (b/c of ↓ RBC production)
- Normal to ↑ megakaryocytes
- Pseudo-Gaucher cells (often)
- ↑ reticulin fibrosis
What are the 3 stages of CML?`
- Chronic or stable
- Accelerated
- Blast crisis
What stage of CML?
- < 10% blasts
Chronic or stable
What stage of CML?
- Poorer response to therapy; more severe anemia; increase in clinical symptoms; micromegakaryocytes; additional c’some abnormalities
- Blasts = 10-19% or
- Promyelocytes and blasts combined = 20%
Accelerated
What stage of CML?
- > 20% blasts; worst prognosis
Blast crisis
In CML blast crisis extramedually tissues such as the liver and spleen are involved; since the stem cell is affected, blasts can go either way ______ or ______
Myeloid; lymphoid
Patients who are Philadelphia Chrom _______ have a worse prognosis than Ph _______ because it progresses more rapidly
Negative; positive
How is CML treated?
- Synthetic tyrosine kinase inhibitors such as Imatinib (Gleevec),
- BM transplant (autologous or allogenic)
- Chemo or alpha-interferon to reduce WBC
This drug competes for the binding site of the BCR-ABL gene and reduces activity of the tyrosine kinase
Imatinib
Chronic Neutrophilic Leukemia is not CML but its close. What is a big difference between the two?
- CNL has an ↑ LAP
- CML has a ↓ LAP
What is Polycythemia Vera’s mutation?
JAK2 V617F
Polycythemia Vera PB findings
Increase in RBCs, neutrophils, platelets
Main clinical presentation of PV
- Pruritus
- Splenomegaly/hepatomegaly
- CNS (headache, tinnitus → thicker blood)
- Blurred vision → thicker blood
- Arterial/venous occlusions (b/c of ↑ platelets)
- ↑ hemorrhagic/thrombotic risk (circulatory problems)
- Dusky/ruddy complexion/plethora
- Peptic ulcers
- Weight loss/fatigue
Main clinical presentation of CML
- Easy fatigability
- Abdominal discomfort
- Weight loss
- Night sweats
- Splenomegaly
- Bone pain/tenderness
- Gout
Polycythemia Vera BM findings
- Hypercellular (but M/E ratio is usually normal)
- ↓ BM iron stores
- ↑ megakaryocytes
- Panmyelosis?
Polycythemia Vera
- Major diagnostic critera (2)
- Hgb > 18.5 g/dL in men; > 16.5 g/dL in women
- Presence of JAK2 V617F or other functionally similar mutation
Polycythemia Vera
- Minor diagnostic criteria (3)
- Hypercellularity in BM for all lineages
- Serum EPO level below reference range
- Endogenous erythroid colony formation in vitro
Three stages of Polycythemia Vera
- Prodromal
- Overt
- Spent
Polycythemia vera
- Therapy
Phlebotomy
Polycythemia Vera
- Prodomal (stable) phase
Borderline to mild erythrocytosis
Polycythemia vera
- Overt phase
Significant increase in red cell mass
Polycythemia Vera
- Spent phase
- Pancytopenia
- Progressive splenomegaly
- BM fibrosis
- Progression to acute leukemia in 15% of patients
Polycythemia Vera
- Pathogenesis
- Pluripotential stem cell clone
- Decline in normal CFU-GM
- Increase in CFU-GEMM
What is EPO more hypersensitive in PV?
Even the smallest amount of EPO will activate RBCs to divide/grow/mature
Polycythemia Vera
- Other helpful findings in diagnosis
- ↑ RBC mass (≥ 36 mL/kg in males; ≥32 mL/kg in females)
- O2 saturation ≥92% (normal)
- Platelets: > 400 x 10^9/L
- Leukocytosis: > 12 X 10^9/L in absence of infection
- ↑ LAP, serum vitamin B12 and binding capacity
- Iron deficiency will lead to M/H presentation
Polycythemia Vera prognosis
- Untreated: 6-18 months
- Treated: 14-18 years
- Secondary cause of erythrocytosis in PV
- Relative cause of erythrocytosis in PV
- Secondary: ↑ RBC (or hemoglobin) as a result of ↓ O2
- Relative: apparent increase in RBCs or hgb due to a decrease in plasma volume
ET female to male ratio?
2:1
What 4 criteria must be met for diagnosing ET?
- Sustained platelet count of > 450 x 10^9/L
- Proliferation of megakaryocytic line in BM w/ ↑ numbers of enlarged, mature megakaryocytes
- Must NOT meet criteria for other MPN, MDS, or myeloid neoplasm
- Positive for JAK2 V617F (found in 40-50% of ET cases)
Other helpful criteria for diagnosis of ET
- Hgb < 13.0 x 10^9/L
- Normal erythrocyte mass; presence of BM iron
- No leukoerythroblastic reaction
- No known cause of reactive thrombocytosis
How to differentiate ET from PV
There is presence of BM iron in ET
How to differentiate ET from CML
There is an absence of the Philadelphia C’some in ET
How to differentiate ET from PMF
There is an absence of marrow collagen fibrosis in ET
Clinical presentation of ET
- Erythromelalgia
- Seizures
- Cerebral or myocardial infarction
- Headache, dizziness, visual disturbances
- Platelet dysfunction
- Thrombosis (extremities, CNS, coronary circulation)
- Hemorrhage (bruising, epistaxis, GI hemorrhage, postoperative hemorrhage)
Essential Thrombocythemia PB findings
- Thrombocytosis (giant, agranular, pseudopods)
- Platelets cluster and accumulate near feather of blood film
- RBCs N/N
- Mature neutrophils may be increased (basophils are not)
Essential Thrombocythemia BM findings
- megakaryocyte hypercellularity (↑ megakaryocyte diameter w/ nuclear hyperlobulation)
- Loose clustering of meagkaryocyte
- ↑ erythropoiesis only if hemorrhaging has occurred
- Normal granulopoiesis
Treatment for Essential Thrombocythemia
Combination of hydroxyurea and low dose aspirin to prevent hemorrhagic and vaso-occlusive complications
Characterized by proliferation of megakaryocytic and granulocytes. At a later stages there is excessive bone marrow fibrosis
Primary Myelofibrosis (PMF)
Other characteristics of PMF
- Myeloid metaplasia (spleen, liver, LNs) = extramedullary hematopoiesis
- Progressive hepato/splenomegaly
- Leukoerythroblastosis
- Myelodysplasia
Three progressive stages of PMF
- Prefibrotic stage
- Early stage
- Fibrotic stage
What happens in the prefibrotic stage of PMF?
- No significant increase in BM fibrosis
- BM is hypercellular w/ increases in neutrophils and megakaryocytes (abnormal forms)
- Neutrophils may have a left shift but usually metas, bands, and segs predominate
What happens in the fibrotic stage of PMF?
- Significant increases in BM fibrosis
- Holistically the BM is hypocellular but there can be focal hypercellular areas
- Abnormal megakaryocytes appear in large clusters
- Acute phase > 20% blasts
PMF lab presentation
- Leukoerythroblastosis (tear drops, nRBC, polychromasia, some macrocytosis, micromegakaryocytes from progressive folate deficiency)
- Granulocytes (immature granulocytes, blasts, dysplastic cells)
- Increased platelets, micromegakaryocytes, and platelet fragments
- JAK2 V617F
- Increased ALP, LDH, uric acid, LAP
PMF BM presentation
Dry tap to fibrosis
- granulocytic and megakaryocytic hyperplasia
- Dysmegakaryopoiesis
- Dysgranulopoiesis
CML may transform into ____
Acute lymphoblastic leukemia
Chronic myelomonocytic leukemia is classified in the WHO system as what?
Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)
